Full text data of DNM1L
DNM1L
(DLP1, DRP1)
[Confidence: low (only semi-automatic identification from reviews)]
Dynamin-1-like protein; 3.6.5.5 (Dnm1p/Vps1p-like protein; DVLP; Dynamin family member proline-rich carboxyl-terminal domain less; Dymple; Dynamin-like protein; Dynamin-like protein 4; Dynamin-like protein IV; HdynIV; Dynamin-related protein 1)
Dynamin-1-like protein; 3.6.5.5 (Dnm1p/Vps1p-like protein; DVLP; Dynamin family member proline-rich carboxyl-terminal domain less; Dymple; Dynamin-like protein; Dynamin-like protein 4; Dynamin-like protein IV; HdynIV; Dynamin-related protein 1)
UniProt
O00429
ID DNM1L_HUMAN Reviewed; 736 AA.
AC O00429; A8K4X9; B4DSU8; O14541; O60709; Q7L6B3; Q8TBT7; Q9BWM1;
read moreAC Q9Y5J2;
DT 10-MAY-2005, integrated into UniProtKB/Swiss-Prot.
DT 06-FEB-2007, sequence version 2.
DT 22-JAN-2014, entry version 120.
DE RecName: Full=Dynamin-1-like protein;
DE EC=3.6.5.5;
DE AltName: Full=Dnm1p/Vps1p-like protein;
DE Short=DVLP;
DE AltName: Full=Dynamin family member proline-rich carboxyl-terminal domain less;
DE Short=Dymple;
DE AltName: Full=Dynamin-like protein;
DE AltName: Full=Dynamin-like protein 4;
DE AltName: Full=Dynamin-like protein IV;
DE Short=HdynIV;
DE AltName: Full=Dynamin-related protein 1;
GN Name=DNM1L; Synonyms=DLP1, DRP1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND SUBCELLULAR LOCATION.
RC TISSUE=Hepatoma;
RX PubMed=9348079;
RA Shin H.-W., Shinotsuka C., Torii S., Murakami K., Nakayama K.;
RT "Identification and subcellular localization of a novel mammalian
RT dynamin-related protein homologous to yeast Vps1p and Dnm1p.";
RL J. Biochem. 122:525-530(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), VARIANT THR-71, TISSUE
RP SPECIFICITY, AND INTERACTION WITH GSK3B.
RC TISSUE=Liver;
RX PubMed=9731200; DOI=10.1006/bbrc.1998.9253;
RA Hong Y.-R., Chen C.-H., Cheng D.-S., Howng S.-L., Chow C.-C.;
RT "Human dynamin-like protein interacts with the glycogen synthase
RT kinase 3beta.";
RL Biochem. Biophys. Res. Commun. 249:697-703(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT THR-71, TISSUE
RP SPECIFICITY, SUBCELLULAR LOCATION, MUTAGENESIS OF LYS-38, AND
RP FUNCTION.
RC TISSUE=Brain;
RX PubMed=9570752;
RA Imoto M., Tachibana I., Urrutia R.;
RT "Identification and functional characterization of a novel human
RT protein highly related to the yeast dynamin-like GTPase Vps1p.";
RL J. Cell Sci. 111:1341-1349(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 3; 4 AND 5), VARIANT THR-71,
RP TISSUE SPECIFICITY, AND INTERACTION WITH GSK3B.
RC TISSUE=Brain;
RX PubMed=10749171; DOI=10.1089/104454900314573;
RA Chen C.-H., Howng S.-L., Hwang S.-L., Chou C.-K., Liao C.-H.,
RA Hong Y.-R.;
RT "Differential expression of four human dynamin-like protein variants
RT in brain tumors.";
RL DNA Cell Biol. 19:189-194(2000).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3 AND 6).
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M.,
RA Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D.,
RA Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z.,
RA Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H.,
RA Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H.,
RA Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V.,
RA Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J.,
RA Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A.,
RA Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M.,
RA Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E.,
RA Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M.,
RA Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R.,
RA Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J.,
RA Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C.,
RA Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M.,
RA Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M.,
RA Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P.,
RA Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L.,
RA Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E.,
RA Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C.,
RA Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F.,
RA Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M.,
RA Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S.,
RA Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D.,
RA Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I.,
RA Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T.,
RA Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S.,
RA Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D.,
RA Kucherlapati R., Weinstock G., Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND NUCLEOTIDE
RP SEQUENCE [LARGE SCALE MRNA] OF 27-736 (ISOFORM 1).
RC TISSUE=Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP MUTAGENESIS OF SER-39, TISSUE SPECIFICITY, CATALYTIC ACTIVITY, AND
RP SUBCELLULAR LOCATION.
RX PubMed=9422767; DOI=10.1074/jbc.273.2.1044;
RA Kamimoto T., Nagai Y., Onogi H., Muro Y., Wakabayashi T., Hagiwara M.;
RT "Dymple, a novel dynamin-like high molecular weight GTPase lacking a
RT proline-rich carboxyl-terminal domain in mammalian cells.";
RL J. Biol. Chem. 273:1044-1051(1998).
RN [9]
RP SUBCELLULAR LOCATION.
RX PubMed=9472031; DOI=10.1083/jcb.140.4.779;
RA Yoon Y., Pitts K.R., Dahan S., McNiven M.A.;
RT "A novel dynamin-like protein associates with cytoplasmic vesicles and
RT tubules of the endoplasmic reticulum in mammalian cells.";
RL J. Cell Biol. 140:779-793(1998).
RN [10]
RP TISSUE SPECIFICITY, SUBCELLULAR LOCATION, AND FUNCTION.
RX PubMed=9786947; DOI=10.1083/jcb.143.2.351;
RA Smirnova E., Shurland D.-L., Ryazantsev S.N., van der Bliek A.M.;
RT "A human dynamin-related protein controls the distribution of
RT mitochondria.";
RL J. Cell Biol. 143:351-358(1998).
RN [11]
RP OLIGOMERIZATION.
RX PubMed=9915810; DOI=10.1074/jbc.274.5.2780;
RA Shin H.-W., Takatsu H., Mukai H., Munekata E., Murakami K.,
RA Nakayama K.;
RT "Intermolecular and interdomain interactions of a dynamin-related GTP-
RT binding protein, Dnm1p/Vps1p-like protein.";
RL J. Biol. Chem. 274:2780-2785(1999).
RN [12]
RP FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF LYS-38; VAL-41; THR-59
RP AND GLY-281, AND OLIGOMERIZATION.
RX PubMed=11514614; DOI=10.1091/mbc.12.8.2245;
RA Smirnova E., Griparic L., Shurland D.-L., van der Bliek A.M.;
RT "Dynamin-related protein Drp1 is required for mitochondrial division
RT in mammalian cells.";
RL Mol. Biol. Cell 12:2245-2256(2001).
RN [13]
RP MUTAGENESIS OF LYS-38, SUBCELLULAR LOCATION, AND FUNCTION.
RX PubMed=12499366; DOI=10.1074/jbc.M211761200;
RA Koch A., Thiemann M., Grabenbauer M., Yoon Y., McNiven M.A.,
RA Schrader M.;
RT "Dynamin-like protein 1 is involved in peroxisomal fission.";
RL J. Biol. Chem. 278:8597-8605(2003).
RN [14]
RP MUTAGENESIS OF SER-39 AND THR-59, FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=12618434; DOI=10.1074/jbc.M212031200;
RA Li X., Gould S.J.;
RT "The dynamin-like GTPase DLP1 is essential for peroxisome division and
RT is recruited to peroxisomes in part by PEX11.";
RL J. Biol. Chem. 278:17012-17020(2003).
RN [15]
RP FUNCTION OF STRUCTURAL DOMAINS, OLIGOMERIZATION, SUBCELLULAR LOCATION,
RP AND MUTAGENESIS OF LYS-38 AND LYS-679.
RX PubMed=15208300; DOI=10.1074/jbc.M404105200;
RA Zhu P.P., Patterson A., Stadler J., Seeburg D.P., Sheng M.,
RA Blackstone C.;
RT "Intra- and intermolecular domain interactions of the C-terminal
RT GTPase effector domain of the multimeric dynamin-like GTPase Drp1.";
RL J. Biol. Chem. 279:35967-35974(2004).
RN [16]
RP UBIQUITINATION BY MARCH5, AND INTERACTION WITH MARCH5.
RX PubMed=16874301; DOI=10.1038/sj.emboj.7601249;
RA Yonashiro R., Ishido S., Kyo S., Fukuda T., Goto E., Matsuki Y.,
RA Ohmura-Hoshino M., Sada K., Hotta H., Yamamura H., Inatome R.,
RA Yanagi S.;
RT "A novel mitochondrial ubiquitin ligase plays a critical role in
RT mitochondrial dynamics.";
RL EMBO J. 25:3618-3626(2006).
RN [17]
RP UBIQUITINATION BY MARCH5, AND INTERACTION WITH MARCH5.
RX PubMed=16936636; DOI=10.1038/sj.embor.7400790;
RA Nakamura N., Kimura Y., Tokuda M., Honda S., Hirose S.;
RT "MARCH-V is a novel mitofusin 2- and Drp1-binding protein able to
RT change mitochondrial morphology.";
RL EMBO Rep. 7:1019-1022(2006).
RN [18]
RP FUNCTION.
RX PubMed=17015472; DOI=10.1128/MCB.02282-05;
RA Parone P.A., James D.I., Da Cruz S., Mattenberger Y., Donze O.,
RA Barja F., Martinou J.C.;
RT "Inhibiting the mitochondrial fission machinery does not prevent
RT Bax/Bak-dependent apoptosis.";
RL Mol. Cell. Biol. 26:7397-7408(2006).
RN [19]
RP PHOSPHORYLATION, AND FUNCTION.
RX PubMed=17301055; DOI=10.1074/jbc.M607279200;
RA Taguchi N., Ishihara N., Jofuku A., Oka T., Mihara K.;
RT "Mitotic phosphorylation of dynamin-related GTPase Drp1 participates
RT in mitochondrial fission.";
RL J. Biol. Chem. 282:11521-11529(2007).
RN [20]
RP PHOSPHORYLATION AT SER-637, FUNCTION, SUBUNIT, AND MUTAGENESIS OF
RP SER-637.
RX PubMed=17553808; DOI=10.1074/jbc.C700083200;
RA Chang C.R., Blackstone C.;
RT "Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates
RT its GTPase activity and mitochondrial morphology.";
RL J. Biol. Chem. 282:21583-21587(2007).
RN [21]
RP SUBCELLULAR LOCATION.
RX PubMed=17606867; DOI=10.1083/jcb.200611064;
RA Karbowski M., Neutzner A., Youle R.J.;
RT "The mitochondrial E3 ubiquitin ligase MARCH5 is required for Drp1
RT dependent mitochondrial division.";
RL J. Cell Biol. 178:71-84(2007).
RN [22]
RP FUNCTION, VARIANT EMPF ASP-395, AND CHARACTERIZATION OF VARIANT EMPF
RP ASP-395.
RX PubMed=17460227; DOI=10.1056/NEJMoa064436;
RA Waterham H.R., Koster J., van Roermund C.W., Mooyer P.A.,
RA Wanders R.J., Leonard J.V.;
RT "A lethal defect of mitochondrial and peroxisomal fission.";
RL N. Engl. J. Med. 356:1736-1741(2007).
RN [23]
RP PHOSPHORYLATION AT SER-637, FUNCTION, INTERACTION WITH FIS1, AND
RP MUTAGENESIS OF SER-637.
RX PubMed=18695047; DOI=10.1083/jcb.200802164;
RA Han X.J., Lu Y.F., Li S.A., Kaitsuka T., Sato Y., Tomizawa K.,
RA Nairn A.C., Takei K., Matsui H., Matsushita M.;
RT "CaM kinase I alpha-induced phosphorylation of Drp1 regulates
RT mitochondrial morphology.";
RL J. Cell Biol. 182:573-585(2008).
RN [24]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-616, AND MASS
RP SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [25]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-548; SER-607 AND
RP SER-616, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [26]
RP PHOSPHORYLATION AT SER-616 AND SER-637, INTERACTION WITH PPP3CA,
RP DEPHOSPHORYLATION, FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP SER-616 AND SER-637.
RX PubMed=18838687; DOI=10.1073/pnas.0808249105;
RA Cereghetti G.M., Stangherlin A., Martins de Brito O., Chang C.R.,
RA Blackstone C., Bernardi P., Scorrano L.;
RT "Dephosphorylation by calcineurin regulates translocation of Drp1 to
RT mitochondria.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:15803-15808(2008).
RN [27]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [28]
RP SUMOYLATION BY MUL1.
RX PubMed=19407830; DOI=10.1038/embor.2009.86;
RA Braschi E., Zunino R., McBride H.M.;
RT "MAPL is a new mitochondrial SUMO E3 ligase that regulates
RT mitochondrial fission.";
RL EMBO Rep. 10:748-754(2009).
RN [29]
RP SUMOYLATION AT LYS-532; LYS-535; LYS-558; LYS-568; LYS-594; LYS-597;
RP LYS-606 AND LYS-608, INTERACTION WITH UBE2I, FUNCTION, AND MUTAGENESIS
RP OF LYS-38; LYS-532; LYS-535; LYS-558; LYS-568; LYS-594; LYS-597;
RP LYS-606 AND LYS-608.
RX PubMed=19638400; DOI=10.1096/fj.09-136630;
RA Figueroa-Romero C., Iniguez-Lluhi J.A., Stadler J., Chang C.R.,
RA Arnoult D., Keller P.J., Hong Y., Blackstone C., Feldman E.L.;
RT "SUMOylation of the mitochondrial fission protein Drp1 occurs at
RT multiple nonconsensus sites within the B domain and is linked to its
RT activity cycle.";
RL FASEB J. 23:3917-3927(2009).
RN [30]
RP SUMOYLATION, DESUMOYLATION, AND FUNCTION.
RX PubMed=19411255; DOI=10.1074/jbc.M901902200;
RA Zunino R., Braschi E., Xu L., McBride H.M.;
RT "Translocation of SenP5 from the nucleoli to the mitochondria
RT modulates DRP1-dependent fission during mitosis.";
RL J. Biol. Chem. 284:17783-17795(2009).
RN [31]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-616, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [32]
RP S-NITROSYLATION AT CYS-644, FUNCTION, ASSOCIATION WITH ALZHEIMER
RP DISEASE, AND MUTAGENESIS OF CYS-300; CYS-345; CYS-361; CYS-367;
RP CYS-431; CYS-446; CYS-470; CYS-505 AND CYS-644.
RX PubMed=19342591; DOI=10.1126/science.1171091;
RA Cho D.H., Nakamura T., Fang J., Cieplak P., Godzik A., Gu Z.,
RA Lipton S.A.;
RT "S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial
RT fission and neuronal injury.";
RL Science 324:102-105(2009).
RN [33]
RP POSSIBLE FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=20688057; DOI=10.1016/j.yexcr.2010.07.020;
RA Bonekamp N.A., Vormund K., Jacob R., Schrader M.;
RT "Dynamin-like protein 1 at the Golgi complex: A novel component of the
RT sorting/targeting machinery en route to the plasma membrane.";
RL Exp. Cell Res. 316:3454-3467(2010).
RN [34]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-616, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [35]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [36]
RP INTERACTION WITH MIEF2 AND MIEF1.
RX PubMed=21508961; DOI=10.1038/embor.2011.54;
RA Palmer C.S., Osellame L.D., Laine D., Koutsopoulos O.S., Frazier A.E.,
RA Ryan M.T.;
RT "MiD49 and MiD51, new components of the mitochondrial fission
RT machinery.";
RL EMBO Rep. 12:565-573(2011).
RN [37]
RP INTERACTION WITH MIEF1.
RX PubMed=21701560; DOI=10.1038/emboj.2011.198;
RA Zhao J., Liu T., Jin S., Wang X., Qu M., Uhlen P., Tomilin N.,
RA Shupliakov O., Lendahl U., Nister M.;
RT "Human MIEF1 recruits Drp1 to mitochondrial outer membranes and
RT promotes mitochondrial fusion rather than fission.";
RL EMBO J. 30:2762-2778(2011).
RN [38]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-616, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [39]
RP INTERACTION WITH PGAM5, AND SUBCELLULAR LOCATION.
RX PubMed=22265414; DOI=10.1016/j.cell.2011.11.030;
RA Wang Z., Jiang H., Chen S., Du F., Wang X.;
RT "The mitochondrial phosphatase PGAM5 functions at the convergence
RT point of multiple necrotic death pathways.";
RL Cell 148:228-243(2012).
RN [40]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=23921378; DOI=10.1074/jbc.M113.479873;
RA Palmer C.S., Elgass K.D., Parton R.G., Osellame L.D., Stojanovski D.,
RA Ryan M.T.;
RT "MiD49 and MiD51 can act independently of Mff and Fis1 in Drp1
RT recruitment and are specific for mitochondrial fission.";
RL J. Biol. Chem. 288:27584-27593(2013).
RN [41]
RP FUNCTION, INTERACTION WITH MIEF2 AND MIEF1, PHOSPHORYLATION AT
RP SER-637, AND MUTAGENESIS OF SER-637.
RX PubMed=23283981; DOI=10.1091/mbc.E12-10-0721;
RA Loson O.C., Song Z., Chen H., Chan D.C.;
RT "Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial
RT fission.";
RL Mol. Biol. Cell 24:659-667(2013).
RN [42]
RP INTERACTION WITH BCL2L1.
RX PubMed=23792689; DOI=10.1038/ncb2791;
RA Li H., Alavian K.N., Lazrove E., Mehta N., Jones A., Zhang P.,
RA Licznerski P., Graham M., Uo T., Guo J., Rahner C., Duman R.S.,
RA Morrison R.S., Jonas E.A.;
RT "A Bcl-xL-Drp1 complex regulates synaptic vesicle membrane dynamics
RT during endocytosis.";
RL Nat. Cell Biol. 15:773-785(2013).
RN [43]
RP FUNCTION, INTERACTION WITH MIEF2, AND SUBUNIT.
RX PubMed=23530241; DOI=10.1073/pnas.1300855110;
RA Koirala S., Guo Q., Kalia R., Bui H.T., Eckert D.M., Frost A.,
RA Shaw J.M.;
RT "Interchangeable adaptors regulate mitochondrial dynamin assembly for
RT membrane scission.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:E1342-E1351(2013).
CC -!- FUNCTION: Functions in mitochondrial and peroxisomal division.
CC Mediates membrane fission through oligomerization into ring-like
CC structures which wrap around the scission site to constict and
CC sever the mitochondrial membrane through a GTP hydrolysis-
CC dependent mechanism. Through its function in mitochondrial
CC division, ensures the survival of at least some types of
CC postmitotic neurons, including Purkinje cells, by suppressing
CC oxidative damage. Required for normal brain development, including
CC that of cerebellum. Facilitates developmentally regulated
CC apoptosis during neural tube formation. Required for a normal rate
CC of cytochrome c release and caspase activation during apoptosis;
CC this requirement may depend upon the cell type and the
CC physiological apoptotic cues. Also required for mitochondrial
CC fission during mitosis. Required for formation of endocytic
CC vesicles. Proposed to regulate synaptic vesicle membrane dynamics
CC through association with BCL2L1 isoform Bcl-X(L) which stimulates
CC its GTPase activity in synaptic vesicles; the function may require
CC its recruitment by MFF to clathrin-containing vesicles. Required
CC for programmed necrosis execution.
CC -!- FUNCTION: Isoform 1 and isoform 4 inhibit peroxisomal division
CC when overexpressed.
CC -!- CATALYTIC ACTIVITY: GTP + H(2)O = GDP + phosphate.
CC -!- SUBUNIT: Homotetramer; dimerizes through the N-terminal GTP-middle
CC region of one molecule binding to the GED domain of another DNM1L
CC molecule. Can self-assemble in multimeric ring-like structures.
CC Interacts with GSK3B and MARCH5. Interacts (via the GTPase and B
CC domains) with UBE2I; the interaction promotes sumoylation of
CC DNM1L, mainly in its B domain. Interacts with PPP3CA; the
CC interaction dephosphorylates DNM1L and regulates its transition to
CC mitochondria. Interacts with BCL2L1 isoform BCL-X(L) and CLTA;
CC DNM1L and BCL2L1 isoform BCL-X(L) may form a complex in synaptic
CC vesicles that also contains clathrin and MFF. Interacts with FIS1.
CC Interacts with MIEF2 and MIEF1. Interacts with PGAM5; this
CC interaction leads to dephosphorylation at Ser-656 and activation
CC of GTPase activity and eventually to mitochondria fragmentation.
CC -!- INTERACTION:
CC P03372:ESR1; NbExp=2; IntAct=EBI-724571, EBI-78473;
CC Q5S007:LRRK2; NbExp=8; IntAct=EBI-724571, EBI-5323863;
CC Q9NQG6:MIEF1; NbExp=9; IntAct=EBI-724571, EBI-740987;
CC Q96C03:MIEF2; NbExp=3; IntAct=EBI-724571, EBI-750153;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol. Golgi apparatus.
CC Endomembrane system; Peripheral membrane protein. Mitochondrion
CC outer membrane; Peripheral membrane protein. Peroxisome. Membrane,
CC clathrin-coated pit (By similarity). Cytoplasmic vesicle,
CC secretory vesicle, synaptic vesicle membrane (By similarity).
CC Note=Mainly cytosolic. Translocated to the mitochondrial membrane
CC through O-GlcNAcylation and interaction with FIS1. Colocalized
CC with MARCH5 at mitochondrial membrane. Localizes to mitochondria
CC at sites of division. Localizes to mitochondria following necrosis
CC induction. Associated with peroxisomal membranes, partly recruited
CC there by PEX11B. May also be associated with endoplasmic reticulum
CC tubules and cytoplasmic vesicles and found to be perinuclear. In
CC some cell types, localizes to the Golgi complex.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=1; Synonyms=HdynIV-WT, DLP1F;
CC IsoId=O00429-1; Sequence=Displayed;
CC Name=4; Synonyms=HdynIV-11, DLP1c;
CC IsoId=O00429-2; Sequence=VSP_013688;
CC Name=2; Synonyms=DLP1a;
CC IsoId=O00429-3; Sequence=VSP_013686;
CC Name=3; Synonyms=HdynIV-37, DLP1b;
CC IsoId=O00429-4; Sequence=VSP_013685;
CC Name=5; Synonyms=HdynIV-26;
CC IsoId=O00429-5; Sequence=VSP_013687;
CC Note=No experimental confirmation available;
CC Name=6;
CC IsoId=O00429-6; Sequence=VSP_039097;
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed with highest levels
CC found in skeletal muscles, heart, kidney and brain. Isoform 1 is
CC brain-specific. Isoform 2 and isoform 3 are predominantly
CC expressed in testis and skeletal muscles respectively. Isoform 4
CC is weakly expressed in brain, heart and kidney. Isoform 5 is
CC dominantly expressed in liver, heart and kidney. Isoform 6 is
CC expressed in neurons.
CC -!- DOMAIN: The GED domain folds back to interact, in cis, with the
CC GTP-binding domain and middle domain, and interacts, in trans,
CC with the GED domains of other DNM1L molecules, and is thus
CC critical for activating GTPase activity and for DNM1L
CC dimerization.
CC -!- PTM: Phosphorylation/dephosphorylation events on two sites near
CC the GED domain regulate mitochondrial fission. Phosphorylation on
CC Ser-637 inhibits mitochondrial fission probably through preventing
CC intramolecular interaction. Dephosphorylated on this site by
CC PPP3CA which promotes mitochondrial fission. Phosphorylation on
CC Ser-616 also promotes mitochondrial fission.
CC -!- PTM: Sumoylated on various lysine residues within the B domain,
CC probably by MUL1. Sumoylation positively regulates mitochondrial
CC fission. Desumoylated by SENP5 during G2/M transition of mitosis.
CC Appears to be linked to its catalytic activity.
CC -!- PTM: S-nitrosylation increases DNM1L dimerization, mitochondrial
CC fission and causes neuronal damage.
CC -!- PTM: Ubiquitination by MARCH5 affects mitochondrial morphology.
CC -!- PTM: O-GlcNAcylation augments the level of the GTP-bound active
CC form of DRP1 and induces translocation from the cytoplasm to
CC mitochondria in cardiomyocytes. It also decreases phosphorylation
CC at Ser-637 (By similarity).
CC -!- DISEASE: Note=May be associated with Alzheimer disease through
CC beta-amyloid-induced increased S-nitrosylation of DNM1L, which
CC triggers, directly or indirectly, excessive mitochondrial fission,
CC synaptic loss and neuronal damage.
CC -!- DISEASE: Encephalopathy, lethal, due to defective mitochondrial
CC and peroxisomal fission (EMPF) [MIM:614388]: A rare autosomal
CC dominant systemic disorder resulting in lack of neurologic
CC development and death in infancy. After birth, infants present in
CC the first week of life with poor feeding and neurologic
CC impairment, including hypotonia, little spontaneous movement, no
CC tendon reflexes, no response to light stimulation, and poor visual
CC fixation. Other features include mildly elevated plasma
CC concentration of very-long-chain fatty acids, lactic acidosis,
CC microcephaly, deep-set eyes, optic atrophy and hypoplasia, and an
CC abnormal gyral pattern in both frontal lobes associated with
CC dysmyelination. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the dynamin family.
CC -!- SIMILARITY: Contains 1 GED domain.
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DR EMBL; AB006965; BAA22193.1; -; mRNA.
DR EMBL; AF061795; AAC35283.1; -; mRNA.
DR EMBL; AF000430; AAC23724.1; -; mRNA.
DR EMBL; AF151685; AAD39541.1; -; mRNA.
DR EMBL; AK299926; BAG61760.1; -; mRNA.
DR EMBL; AK291094; BAF83783.1; -; mRNA.
DR EMBL; AC084824; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC087588; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC024590; AAH24590.1; -; mRNA.
DR PIR; JC5695; JC5695.
DR RefSeq; NP_001265392.1; NM_001278463.1.
DR RefSeq; NP_001265393.1; NM_001278464.1.
DR RefSeq; NP_005681.2; NM_005690.4.
DR RefSeq; NP_036192.2; NM_012062.4.
DR RefSeq; NP_036193.2; NM_012063.3.
DR UniGene; Hs.556296; -.
DR PDB; 4BEJ; X-ray; 3.48 A; A/B/C/D=1-736.
DR PDB; 4H1U; X-ray; 2.30 A; A=711-736.
DR PDB; 4H1V; X-ray; 2.30 A; A=2-327.
DR PDBsum; 4BEJ; -.
DR PDBsum; 4H1U; -.
DR PDBsum; 4H1V; -.
DR ProteinModelPortal; O00429; -.
DR SMR; O00429; 1-504, 642-729.
DR IntAct; O00429; 12.
DR MINT; MINT-1394198; -.
DR STRING; 9606.ENSP00000266481; -.
DR PhosphoSite; O00429; -.
DR PaxDb; O00429; -.
DR PRIDE; O00429; -.
DR DNASU; 10059; -.
DR Ensembl; ENST00000266481; ENSP00000266481; ENSG00000087470.
DR Ensembl; ENST00000452533; ENSP00000415131; ENSG00000087470.
DR Ensembl; ENST00000547312; ENSP00000448610; ENSG00000087470.
DR Ensembl; ENST00000549701; ENSP00000450399; ENSG00000087470.
DR Ensembl; ENST00000553257; ENSP00000449089; ENSG00000087470.
DR GeneID; 10059; -.
DR KEGG; hsa:10059; -.
DR UCSC; uc001rld.2; human.
DR CTD; 10059; -.
DR GeneCards; GC12P032832; -.
DR H-InvDB; HIX0010537; -.
DR HGNC; HGNC:2973; DNM1L.
DR HPA; CAB009952; -.
DR MIM; 603850; gene.
DR MIM; 614388; phenotype.
DR neXtProt; NX_O00429; -.
DR Orphanet; 330050; Lethal encephalopathy due to mitochondrial and peroxisomal fission defect.
DR PharmGKB; PA27441; -.
DR eggNOG; COG0699; -.
DR HOVERGEN; HBG107833; -.
DR KO; K17065; -.
DR OMA; RDKSYKV; -.
DR OrthoDB; EOG7GJ6CB; -.
DR PhylomeDB; O00429; -.
DR Reactome; REACT_578; Apoptosis.
DR ChiTaRS; DNM1L; human.
DR GeneWiki; DNM1L; -.
DR GenomeRNAi; 10059; -.
DR NextBio; 38007; -.
DR PMAP-CutDB; O00429; -.
DR PRO; PR:O00429; -.
DR ArrayExpress; O00429; -.
DR Bgee; O00429; -.
DR CleanEx; HS_DNM1L; -.
DR Genevestigator; O00429; -.
DR GO; GO:0030054; C:cell junction; IEA:UniProtKB-KW.
DR GO; GO:0005905; C:coated pit; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
DR GO; GO:0005874; C:microtubule; IDA:UniProtKB.
DR GO; GO:0005741; C:mitochondrial outer membrane; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0005777; C:peroxisome; IDA:UniProtKB.
DR GO; GO:0043234; C:protein complex; IDA:UniProtKB.
DR GO; GO:0030672; C:synaptic vesicle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW.
DR GO; GO:0003924; F:GTPase activity; IDA:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0006921; P:cellular component disassembly involved in execution phase of apoptosis; TAS:Reactome.
DR GO; GO:0003374; P:dynamin polymerization involved in mitochondrial fission; IDA:UniProtKB.
DR GO; GO:0006897; P:endocytosis; IEA:UniProtKB-KW.
DR GO; GO:0090149; P:membrane fission involved in mitochondrial fission; IDA:UniProtKB.
DR GO; GO:0043653; P:mitochondrial fragmentation involved in apoptotic process; IMP:UniProtKB.
DR GO; GO:0070584; P:mitochondrion morphogenesis; IMP:MGI.
DR GO; GO:0070266; P:necroptotic process; IMP:UniProtKB.
DR GO; GO:0016559; P:peroxisome fission; IDA:UniProtKB.
DR GO; GO:2001244; P:positive regulation of intrinsic apoptotic signaling pathway; IMP:UniProtKB.
DR GO; GO:0090141; P:positive regulation of mitochondrial fission; TAS:BHF-UCL.
DR GO; GO:0050714; P:positive regulation of protein secretion; IDA:UniProtKB.
DR GO; GO:0090200; P:positive regulation of release of cytochrome c from mitochondria; IMP:UniProtKB.
DR GO; GO:0051289; P:protein homotetramerization; IDA:UniProtKB.
DR GO; GO:1900063; P:regulation of peroxisome organization; IMP:UniProtKB.
DR InterPro; IPR000375; Dynamin_central.
DR InterPro; IPR001401; Dynamin_GTPase.
DR InterPro; IPR019762; Dynamin_GTPase_CS.
DR InterPro; IPR022812; Dynamin_SF.
DR InterPro; IPR003130; GED.
DR InterPro; IPR020850; GTPase_effector_domain_GED.
DR InterPro; IPR027417; P-loop_NTPase.
DR PANTHER; PTHR11566; PTHR11566; 1.
DR Pfam; PF01031; Dynamin_M; 1.
DR Pfam; PF00350; Dynamin_N; 1.
DR Pfam; PF02212; GED; 1.
DR PRINTS; PR00195; DYNAMIN.
DR SMART; SM00053; DYNc; 1.
DR SMART; SM00302; GED; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR PROSITE; PS00410; DYNAMIN; 1.
DR PROSITE; PS51388; GED; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Cell junction;
KW Coated pit; Complete proteome; Cytoplasm; Cytoplasmic vesicle;
KW Disease mutation; Endocytosis; Glycoprotein; Golgi apparatus;
KW GTP-binding; Hydrolase; Isopeptide bond; Membrane; Mitochondrion;
KW Mitochondrion outer membrane; Necrosis; Nucleotide-binding;
KW Peroxisome; Phosphoprotein; Polymorphism; Reference proteome;
KW S-nitrosylation; Synapse; Ubl conjugation.
FT CHAIN 1 736 Dynamin-1-like protein.
FT /FTId=PRO_0000206566.
FT DOMAIN 644 735 GED.
FT NP_BIND 32 39 GTP (By similarity).
FT NP_BIND 146 150 GTP (By similarity).
FT NP_BIND 215 218 GTP (By similarity).
FT REGION 1 343 GTPase domain.
FT REGION 344 489 Middle domain.
FT REGION 448 685 Interaction with GSK3B.
FT REGION 502 569 B domain.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 548 548 Phosphoserine.
FT MOD_RES 607 607 Phosphoserine.
FT MOD_RES 616 616 Phosphoserine; by CDK1.
FT MOD_RES 637 637 Phosphoserine; by CAMK1 and PKA.
FT MOD_RES 644 644 S-nitrosocysteine.
FT CARBOHYD 585 585 O-linked (GlcNAc) (By similarity).
FT CARBOHYD 586 586 O-linked (GlcNAc) (By similarity).
FT CROSSLNK 532 532 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO).
FT CROSSLNK 535 535 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO).
FT CROSSLNK 558 558 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO).
FT CROSSLNK 568 568 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO).
FT CROSSLNK 594 594 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO)
FT (Probable).
FT CROSSLNK 597 597 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO).
FT CROSSLNK 606 606 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO)
FT (Probable).
FT CROSSLNK 608 608 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO).
FT VAR_SEQ 83 83 N -> NDPATWKNSRHLSK (in isoform 6).
FT /FTId=VSP_039097.
FT VAR_SEQ 533 569 Missing (in isoform 3).
FT /FTId=VSP_013685.
FT VAR_SEQ 533 558 Missing (in isoform 2).
FT /FTId=VSP_013686.
FT VAR_SEQ 544 569 Missing (in isoform 5).
FT /FTId=VSP_013687.
FT VAR_SEQ 559 569 Missing (in isoform 4).
FT /FTId=VSP_013688.
FT VARIANT 71 71 S -> T (in dbSNP:rs1064610).
FT /FTId=VAR_022446.
FT VARIANT 395 395 A -> D (in EMPF; the mutation acts in a
FT dominant-negative manner; defects
FT observed in both mitochondrial and
FT peroxisomal fission).
FT /FTId=VAR_063704.
FT VARIANT 426 426 E -> D (in dbSNP:rs2389105).
FT /FTId=VAR_030489.
FT MUTAGEN 38 38 K->A: Loss of GTPase activity. Impairs
FT mitochondrial division and induces
FT changes in peroxisome morphology. No
FT effect on oligomerization. Increase in
FT sumoylation by SUMO3.
FT MUTAGEN 38 38 K->E: Overexpression delays protein
FT secretion.
FT MUTAGEN 39 39 S->I: Decreased localization to the
FT perinuclear region.
FT MUTAGEN 39 39 S->N: Reduces peroxisomal abundance.
FT MUTAGEN 41 41 V->F: Temperature-sensitive. Impairs
FT mitochondrial division.
FT MUTAGEN 59 59 T->A: Impairs mitochondrial division.
FT Reduces peroxisomal abundance.
FT MUTAGEN 281 281 G->D: Temperature-sensitive. Impairs
FT mitochondrial division.
FT MUTAGEN 300 300 C->A: No effect on S-nitrosylation.
FT MUTAGEN 345 345 C->A: No effect on S-nitrosylation.
FT MUTAGEN 361 361 C->A: No effect on S-nitrosylation.
FT MUTAGEN 367 367 C->A: No effect on S-nitrosylation.
FT MUTAGEN 431 431 C->A: No effect on S-nitrosylation.
FT MUTAGEN 446 446 C->A: No effect on S-nitrosylation.
FT MUTAGEN 470 470 C->A: No effect on S-nitrosylation.
FT MUTAGEN 505 505 C->A: No effect on S-nitrosylation.
FT MUTAGEN 532 532 K->R: Some loss of sumoylation in B
FT domain. Complete loss of sumoylation in B
FT domain; when associated with R-535; R-558
FT and R-568.
FT MUTAGEN 535 535 K->R: Some loss of sumoylation in B
FT domain. Complete loss of sumoylation in B
FT domain; when associated with R-532; R-558
FT and R-568.
FT MUTAGEN 558 558 K->R: Some loss of sumoylation in B
FT domain. Complete loss of sumoylation in B
FT domain; when associated with R-532; R-535
FT and R-568.
FT MUTAGEN 568 568 K->R: Some loss of sumoylation in B
FT domain. Complete loss of sumoylation in B
FT domain; when associated with R-532; R-535
FT and R-558.
FT MUTAGEN 594 594 K->R: Some loss of sumoylation in the GED
FT domain; Complete loss of sumoylation in
FT the GED domain; when associated with R-
FT 597; R-606 and R-608.
FT MUTAGEN 597 597 K->R: Some loss of sumoylation in the GED
FT domain; Complete loss of sumoylation in
FT the GED domain; when associated with R-
FT 594; R-606 and R-608.
FT MUTAGEN 606 606 K->R: Some loss of sumoylation in the GED
FT domain; Complete loss of sumoylation in
FT the GED domain; when associated with R-
FT 594; R-597 and R-608.
FT MUTAGEN 608 608 K->R: Some loss of sumoylation in the GED
FT domain; Complete loss of sumoylation in
FT the GED domain; when associated with R-
FT 594; R-597 and R-606.
FT MUTAGEN 616 616 S->A: Little effect on mitochondrial
FT morphology. Translocated to mitochondria.
FT MUTAGEN 637 637 S->A: Abolishes phosphorylation. Reduces
FT interaction with MIEF1 and MIEF2.
FT Promotes mitochondrial fission and cell
FT vulnerability to apoptotic insults.
FT Mostly mitochondrial. Disrupts, in vitro,
FT binding to FIS1.
FT MUTAGEN 637 637 S->D: Impairs intramolecular, but not
FT intermolecular interactions. Slight
FT reduction in GTPase activity. Does not
FT reduce interaction with MIEF1 and MIEF2.
FT Inhibits mitochondrial fission. Retained
FT in cytoplasm.
FT MUTAGEN 644 644 C->A: Abolishes S-nitrosylation. Reduced
FT dimerization and no enhancement of GTPase
FT activity.
FT MUTAGEN 679 679 K->A: Diminishes intermolecular
FT interaction between GTP-middle domain and
FT GED domain but no effect on
FT oligomerization. Marked reduction in
FT GTPase activity, in vitro. Decreased
FT mitochondrial division.
FT CONFLICT 208 208 R -> C (in Ref. 2; AAC35283 and 4;
FT AAD39541).
FT HELIX 5 14
FT TURN 15 18
FT TURN 21 23
FT STRAND 27 33
FT HELIX 34 36
FT HELIX 38 46
FT STRAND 55 57
FT STRAND 63 69
FT STRAND 86 88
FT STRAND 90 94
FT TURN 95 98
FT HELIX 104 112
FT STRAND 115 117
FT STRAND 120 124
FT STRAND 130 136
FT STRAND 141 146
FT HELIX 155 157
FT HELIX 163 174
FT STRAND 179 186
FT HELIX 191 193
FT HELIX 195 200
FT TURN 201 203
FT STRAND 205 207
FT STRAND 210 215
FT HELIX 217 219
FT STRAND 222 225
FT HELIX 227 230
FT STRAND 233 235
FT STRAND 237 239
FT STRAND 241 243
FT HELIX 249 253
FT HELIX 258 272
FT TURN 274 276
FT HELIX 277 279
FT HELIX 282 322
FT HELIX 329 349
FT HELIX 363 371
FT HELIX 373 380
FT HELIX 389 399
FT HELIX 409 420
FT HELIX 421 424
FT HELIX 425 440
FT TURN 441 443
FT HELIX 444 446
FT HELIX 458 493
FT HELIX 501 504
FT HELIX 632 662
FT HELIX 664 679
FT HELIX 682 688
FT HELIX 711 728
SQ SEQUENCE 736 AA; 81877 MW; F9521A376B785B71 CRC64;
MEALIPVINK LQDVFNTVGA DIIQLPQIVV VGTQSSGKSS VLESLVGRDL LPRGTGIVTR
RPLILQLVHV SQEDKRKTTG EENGVEAEEW GKFLHTKNKL YTDFDEIRQE IENETERISG
NNKGVSPEPI HLKIFSPNVV NLTLVDLPGM TKVPVGDQPK DIELQIRELI LRFISNPNSI
ILAVTAANTD MATSEALKIS REVDPDGRRT LAVITKLDLM DAGTDAMDVL MGRVIPVKLG
IIGVVNRSQL DINNKKSVTD SIRDEYAFLQ KKYPSLANRN GTKYLARTLN RLLMHHIRDC
LPELKTRINV LAAQYQSLLN SYGEPVDDKS ATLLQLITKF ATEYCNTIEG TAKYIETSEL
CGGARICYIF HETFGRTLES VDPLGGLNTI DILTAIRNAT GPRPALFVPE VSFELLVKRQ
IKRLEEPSLR CVELVHEEMQ RIIQHCSNYS TQELLRFPKL HDAIVEVVTC LLRKRLPVTN
EMVHNLVAIE LAYINTKHPD FADACGLMNN NIEEQRRNRL ARELPSAVSR DKSSKVPSAL
APASQEPSPA ASAEADGKLI QDSRRETKNV ASGGGGVGDG VQEPTTGNWR GMLKTSKAEE
LLAEEKSKPI PIMPASPQKG HAVNLLDVPV PVARKLSARE QRDCEVIERL IKSYFLIVRK
NIQDSVPKAV MHFLVNHVKD TLQSELVGQL YKSSLLDDLL TESEDMAQRR KEAADMLKAL
QGASQIIAEI RETHLW
//
ID DNM1L_HUMAN Reviewed; 736 AA.
AC O00429; A8K4X9; B4DSU8; O14541; O60709; Q7L6B3; Q8TBT7; Q9BWM1;
read moreAC Q9Y5J2;
DT 10-MAY-2005, integrated into UniProtKB/Swiss-Prot.
DT 06-FEB-2007, sequence version 2.
DT 22-JAN-2014, entry version 120.
DE RecName: Full=Dynamin-1-like protein;
DE EC=3.6.5.5;
DE AltName: Full=Dnm1p/Vps1p-like protein;
DE Short=DVLP;
DE AltName: Full=Dynamin family member proline-rich carboxyl-terminal domain less;
DE Short=Dymple;
DE AltName: Full=Dynamin-like protein;
DE AltName: Full=Dynamin-like protein 4;
DE AltName: Full=Dynamin-like protein IV;
DE Short=HdynIV;
DE AltName: Full=Dynamin-related protein 1;
GN Name=DNM1L; Synonyms=DLP1, DRP1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND SUBCELLULAR LOCATION.
RC TISSUE=Hepatoma;
RX PubMed=9348079;
RA Shin H.-W., Shinotsuka C., Torii S., Murakami K., Nakayama K.;
RT "Identification and subcellular localization of a novel mammalian
RT dynamin-related protein homologous to yeast Vps1p and Dnm1p.";
RL J. Biochem. 122:525-530(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), VARIANT THR-71, TISSUE
RP SPECIFICITY, AND INTERACTION WITH GSK3B.
RC TISSUE=Liver;
RX PubMed=9731200; DOI=10.1006/bbrc.1998.9253;
RA Hong Y.-R., Chen C.-H., Cheng D.-S., Howng S.-L., Chow C.-C.;
RT "Human dynamin-like protein interacts with the glycogen synthase
RT kinase 3beta.";
RL Biochem. Biophys. Res. Commun. 249:697-703(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT THR-71, TISSUE
RP SPECIFICITY, SUBCELLULAR LOCATION, MUTAGENESIS OF LYS-38, AND
RP FUNCTION.
RC TISSUE=Brain;
RX PubMed=9570752;
RA Imoto M., Tachibana I., Urrutia R.;
RT "Identification and functional characterization of a novel human
RT protein highly related to the yeast dynamin-like GTPase Vps1p.";
RL J. Cell Sci. 111:1341-1349(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 3; 4 AND 5), VARIANT THR-71,
RP TISSUE SPECIFICITY, AND INTERACTION WITH GSK3B.
RC TISSUE=Brain;
RX PubMed=10749171; DOI=10.1089/104454900314573;
RA Chen C.-H., Howng S.-L., Hwang S.-L., Chou C.-K., Liao C.-H.,
RA Hong Y.-R.;
RT "Differential expression of four human dynamin-like protein variants
RT in brain tumors.";
RL DNA Cell Biol. 19:189-194(2000).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3 AND 6).
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M.,
RA Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D.,
RA Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z.,
RA Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H.,
RA Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H.,
RA Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V.,
RA Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J.,
RA Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A.,
RA Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M.,
RA Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E.,
RA Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M.,
RA Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R.,
RA Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J.,
RA Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C.,
RA Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M.,
RA Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M.,
RA Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P.,
RA Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L.,
RA Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E.,
RA Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C.,
RA Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F.,
RA Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M.,
RA Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S.,
RA Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D.,
RA Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I.,
RA Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T.,
RA Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S.,
RA Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D.,
RA Kucherlapati R., Weinstock G., Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND NUCLEOTIDE
RP SEQUENCE [LARGE SCALE MRNA] OF 27-736 (ISOFORM 1).
RC TISSUE=Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP MUTAGENESIS OF SER-39, TISSUE SPECIFICITY, CATALYTIC ACTIVITY, AND
RP SUBCELLULAR LOCATION.
RX PubMed=9422767; DOI=10.1074/jbc.273.2.1044;
RA Kamimoto T., Nagai Y., Onogi H., Muro Y., Wakabayashi T., Hagiwara M.;
RT "Dymple, a novel dynamin-like high molecular weight GTPase lacking a
RT proline-rich carboxyl-terminal domain in mammalian cells.";
RL J. Biol. Chem. 273:1044-1051(1998).
RN [9]
RP SUBCELLULAR LOCATION.
RX PubMed=9472031; DOI=10.1083/jcb.140.4.779;
RA Yoon Y., Pitts K.R., Dahan S., McNiven M.A.;
RT "A novel dynamin-like protein associates with cytoplasmic vesicles and
RT tubules of the endoplasmic reticulum in mammalian cells.";
RL J. Cell Biol. 140:779-793(1998).
RN [10]
RP TISSUE SPECIFICITY, SUBCELLULAR LOCATION, AND FUNCTION.
RX PubMed=9786947; DOI=10.1083/jcb.143.2.351;
RA Smirnova E., Shurland D.-L., Ryazantsev S.N., van der Bliek A.M.;
RT "A human dynamin-related protein controls the distribution of
RT mitochondria.";
RL J. Cell Biol. 143:351-358(1998).
RN [11]
RP OLIGOMERIZATION.
RX PubMed=9915810; DOI=10.1074/jbc.274.5.2780;
RA Shin H.-W., Takatsu H., Mukai H., Munekata E., Murakami K.,
RA Nakayama K.;
RT "Intermolecular and interdomain interactions of a dynamin-related GTP-
RT binding protein, Dnm1p/Vps1p-like protein.";
RL J. Biol. Chem. 274:2780-2785(1999).
RN [12]
RP FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF LYS-38; VAL-41; THR-59
RP AND GLY-281, AND OLIGOMERIZATION.
RX PubMed=11514614; DOI=10.1091/mbc.12.8.2245;
RA Smirnova E., Griparic L., Shurland D.-L., van der Bliek A.M.;
RT "Dynamin-related protein Drp1 is required for mitochondrial division
RT in mammalian cells.";
RL Mol. Biol. Cell 12:2245-2256(2001).
RN [13]
RP MUTAGENESIS OF LYS-38, SUBCELLULAR LOCATION, AND FUNCTION.
RX PubMed=12499366; DOI=10.1074/jbc.M211761200;
RA Koch A., Thiemann M., Grabenbauer M., Yoon Y., McNiven M.A.,
RA Schrader M.;
RT "Dynamin-like protein 1 is involved in peroxisomal fission.";
RL J. Biol. Chem. 278:8597-8605(2003).
RN [14]
RP MUTAGENESIS OF SER-39 AND THR-59, FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=12618434; DOI=10.1074/jbc.M212031200;
RA Li X., Gould S.J.;
RT "The dynamin-like GTPase DLP1 is essential for peroxisome division and
RT is recruited to peroxisomes in part by PEX11.";
RL J. Biol. Chem. 278:17012-17020(2003).
RN [15]
RP FUNCTION OF STRUCTURAL DOMAINS, OLIGOMERIZATION, SUBCELLULAR LOCATION,
RP AND MUTAGENESIS OF LYS-38 AND LYS-679.
RX PubMed=15208300; DOI=10.1074/jbc.M404105200;
RA Zhu P.P., Patterson A., Stadler J., Seeburg D.P., Sheng M.,
RA Blackstone C.;
RT "Intra- and intermolecular domain interactions of the C-terminal
RT GTPase effector domain of the multimeric dynamin-like GTPase Drp1.";
RL J. Biol. Chem. 279:35967-35974(2004).
RN [16]
RP UBIQUITINATION BY MARCH5, AND INTERACTION WITH MARCH5.
RX PubMed=16874301; DOI=10.1038/sj.emboj.7601249;
RA Yonashiro R., Ishido S., Kyo S., Fukuda T., Goto E., Matsuki Y.,
RA Ohmura-Hoshino M., Sada K., Hotta H., Yamamura H., Inatome R.,
RA Yanagi S.;
RT "A novel mitochondrial ubiquitin ligase plays a critical role in
RT mitochondrial dynamics.";
RL EMBO J. 25:3618-3626(2006).
RN [17]
RP UBIQUITINATION BY MARCH5, AND INTERACTION WITH MARCH5.
RX PubMed=16936636; DOI=10.1038/sj.embor.7400790;
RA Nakamura N., Kimura Y., Tokuda M., Honda S., Hirose S.;
RT "MARCH-V is a novel mitofusin 2- and Drp1-binding protein able to
RT change mitochondrial morphology.";
RL EMBO Rep. 7:1019-1022(2006).
RN [18]
RP FUNCTION.
RX PubMed=17015472; DOI=10.1128/MCB.02282-05;
RA Parone P.A., James D.I., Da Cruz S., Mattenberger Y., Donze O.,
RA Barja F., Martinou J.C.;
RT "Inhibiting the mitochondrial fission machinery does not prevent
RT Bax/Bak-dependent apoptosis.";
RL Mol. Cell. Biol. 26:7397-7408(2006).
RN [19]
RP PHOSPHORYLATION, AND FUNCTION.
RX PubMed=17301055; DOI=10.1074/jbc.M607279200;
RA Taguchi N., Ishihara N., Jofuku A., Oka T., Mihara K.;
RT "Mitotic phosphorylation of dynamin-related GTPase Drp1 participates
RT in mitochondrial fission.";
RL J. Biol. Chem. 282:11521-11529(2007).
RN [20]
RP PHOSPHORYLATION AT SER-637, FUNCTION, SUBUNIT, AND MUTAGENESIS OF
RP SER-637.
RX PubMed=17553808; DOI=10.1074/jbc.C700083200;
RA Chang C.R., Blackstone C.;
RT "Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates
RT its GTPase activity and mitochondrial morphology.";
RL J. Biol. Chem. 282:21583-21587(2007).
RN [21]
RP SUBCELLULAR LOCATION.
RX PubMed=17606867; DOI=10.1083/jcb.200611064;
RA Karbowski M., Neutzner A., Youle R.J.;
RT "The mitochondrial E3 ubiquitin ligase MARCH5 is required for Drp1
RT dependent mitochondrial division.";
RL J. Cell Biol. 178:71-84(2007).
RN [22]
RP FUNCTION, VARIANT EMPF ASP-395, AND CHARACTERIZATION OF VARIANT EMPF
RP ASP-395.
RX PubMed=17460227; DOI=10.1056/NEJMoa064436;
RA Waterham H.R., Koster J., van Roermund C.W., Mooyer P.A.,
RA Wanders R.J., Leonard J.V.;
RT "A lethal defect of mitochondrial and peroxisomal fission.";
RL N. Engl. J. Med. 356:1736-1741(2007).
RN [23]
RP PHOSPHORYLATION AT SER-637, FUNCTION, INTERACTION WITH FIS1, AND
RP MUTAGENESIS OF SER-637.
RX PubMed=18695047; DOI=10.1083/jcb.200802164;
RA Han X.J., Lu Y.F., Li S.A., Kaitsuka T., Sato Y., Tomizawa K.,
RA Nairn A.C., Takei K., Matsui H., Matsushita M.;
RT "CaM kinase I alpha-induced phosphorylation of Drp1 regulates
RT mitochondrial morphology.";
RL J. Cell Biol. 182:573-585(2008).
RN [24]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-616, AND MASS
RP SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [25]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-548; SER-607 AND
RP SER-616, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [26]
RP PHOSPHORYLATION AT SER-616 AND SER-637, INTERACTION WITH PPP3CA,
RP DEPHOSPHORYLATION, FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP SER-616 AND SER-637.
RX PubMed=18838687; DOI=10.1073/pnas.0808249105;
RA Cereghetti G.M., Stangherlin A., Martins de Brito O., Chang C.R.,
RA Blackstone C., Bernardi P., Scorrano L.;
RT "Dephosphorylation by calcineurin regulates translocation of Drp1 to
RT mitochondria.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:15803-15808(2008).
RN [27]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [28]
RP SUMOYLATION BY MUL1.
RX PubMed=19407830; DOI=10.1038/embor.2009.86;
RA Braschi E., Zunino R., McBride H.M.;
RT "MAPL is a new mitochondrial SUMO E3 ligase that regulates
RT mitochondrial fission.";
RL EMBO Rep. 10:748-754(2009).
RN [29]
RP SUMOYLATION AT LYS-532; LYS-535; LYS-558; LYS-568; LYS-594; LYS-597;
RP LYS-606 AND LYS-608, INTERACTION WITH UBE2I, FUNCTION, AND MUTAGENESIS
RP OF LYS-38; LYS-532; LYS-535; LYS-558; LYS-568; LYS-594; LYS-597;
RP LYS-606 AND LYS-608.
RX PubMed=19638400; DOI=10.1096/fj.09-136630;
RA Figueroa-Romero C., Iniguez-Lluhi J.A., Stadler J., Chang C.R.,
RA Arnoult D., Keller P.J., Hong Y., Blackstone C., Feldman E.L.;
RT "SUMOylation of the mitochondrial fission protein Drp1 occurs at
RT multiple nonconsensus sites within the B domain and is linked to its
RT activity cycle.";
RL FASEB J. 23:3917-3927(2009).
RN [30]
RP SUMOYLATION, DESUMOYLATION, AND FUNCTION.
RX PubMed=19411255; DOI=10.1074/jbc.M901902200;
RA Zunino R., Braschi E., Xu L., McBride H.M.;
RT "Translocation of SenP5 from the nucleoli to the mitochondria
RT modulates DRP1-dependent fission during mitosis.";
RL J. Biol. Chem. 284:17783-17795(2009).
RN [31]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-616, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [32]
RP S-NITROSYLATION AT CYS-644, FUNCTION, ASSOCIATION WITH ALZHEIMER
RP DISEASE, AND MUTAGENESIS OF CYS-300; CYS-345; CYS-361; CYS-367;
RP CYS-431; CYS-446; CYS-470; CYS-505 AND CYS-644.
RX PubMed=19342591; DOI=10.1126/science.1171091;
RA Cho D.H., Nakamura T., Fang J., Cieplak P., Godzik A., Gu Z.,
RA Lipton S.A.;
RT "S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial
RT fission and neuronal injury.";
RL Science 324:102-105(2009).
RN [33]
RP POSSIBLE FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=20688057; DOI=10.1016/j.yexcr.2010.07.020;
RA Bonekamp N.A., Vormund K., Jacob R., Schrader M.;
RT "Dynamin-like protein 1 at the Golgi complex: A novel component of the
RT sorting/targeting machinery en route to the plasma membrane.";
RL Exp. Cell Res. 316:3454-3467(2010).
RN [34]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-616, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [35]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [36]
RP INTERACTION WITH MIEF2 AND MIEF1.
RX PubMed=21508961; DOI=10.1038/embor.2011.54;
RA Palmer C.S., Osellame L.D., Laine D., Koutsopoulos O.S., Frazier A.E.,
RA Ryan M.T.;
RT "MiD49 and MiD51, new components of the mitochondrial fission
RT machinery.";
RL EMBO Rep. 12:565-573(2011).
RN [37]
RP INTERACTION WITH MIEF1.
RX PubMed=21701560; DOI=10.1038/emboj.2011.198;
RA Zhao J., Liu T., Jin S., Wang X., Qu M., Uhlen P., Tomilin N.,
RA Shupliakov O., Lendahl U., Nister M.;
RT "Human MIEF1 recruits Drp1 to mitochondrial outer membranes and
RT promotes mitochondrial fusion rather than fission.";
RL EMBO J. 30:2762-2778(2011).
RN [38]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-616, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [39]
RP INTERACTION WITH PGAM5, AND SUBCELLULAR LOCATION.
RX PubMed=22265414; DOI=10.1016/j.cell.2011.11.030;
RA Wang Z., Jiang H., Chen S., Du F., Wang X.;
RT "The mitochondrial phosphatase PGAM5 functions at the convergence
RT point of multiple necrotic death pathways.";
RL Cell 148:228-243(2012).
RN [40]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=23921378; DOI=10.1074/jbc.M113.479873;
RA Palmer C.S., Elgass K.D., Parton R.G., Osellame L.D., Stojanovski D.,
RA Ryan M.T.;
RT "MiD49 and MiD51 can act independently of Mff and Fis1 in Drp1
RT recruitment and are specific for mitochondrial fission.";
RL J. Biol. Chem. 288:27584-27593(2013).
RN [41]
RP FUNCTION, INTERACTION WITH MIEF2 AND MIEF1, PHOSPHORYLATION AT
RP SER-637, AND MUTAGENESIS OF SER-637.
RX PubMed=23283981; DOI=10.1091/mbc.E12-10-0721;
RA Loson O.C., Song Z., Chen H., Chan D.C.;
RT "Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial
RT fission.";
RL Mol. Biol. Cell 24:659-667(2013).
RN [42]
RP INTERACTION WITH BCL2L1.
RX PubMed=23792689; DOI=10.1038/ncb2791;
RA Li H., Alavian K.N., Lazrove E., Mehta N., Jones A., Zhang P.,
RA Licznerski P., Graham M., Uo T., Guo J., Rahner C., Duman R.S.,
RA Morrison R.S., Jonas E.A.;
RT "A Bcl-xL-Drp1 complex regulates synaptic vesicle membrane dynamics
RT during endocytosis.";
RL Nat. Cell Biol. 15:773-785(2013).
RN [43]
RP FUNCTION, INTERACTION WITH MIEF2, AND SUBUNIT.
RX PubMed=23530241; DOI=10.1073/pnas.1300855110;
RA Koirala S., Guo Q., Kalia R., Bui H.T., Eckert D.M., Frost A.,
RA Shaw J.M.;
RT "Interchangeable adaptors regulate mitochondrial dynamin assembly for
RT membrane scission.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:E1342-E1351(2013).
CC -!- FUNCTION: Functions in mitochondrial and peroxisomal division.
CC Mediates membrane fission through oligomerization into ring-like
CC structures which wrap around the scission site to constict and
CC sever the mitochondrial membrane through a GTP hydrolysis-
CC dependent mechanism. Through its function in mitochondrial
CC division, ensures the survival of at least some types of
CC postmitotic neurons, including Purkinje cells, by suppressing
CC oxidative damage. Required for normal brain development, including
CC that of cerebellum. Facilitates developmentally regulated
CC apoptosis during neural tube formation. Required for a normal rate
CC of cytochrome c release and caspase activation during apoptosis;
CC this requirement may depend upon the cell type and the
CC physiological apoptotic cues. Also required for mitochondrial
CC fission during mitosis. Required for formation of endocytic
CC vesicles. Proposed to regulate synaptic vesicle membrane dynamics
CC through association with BCL2L1 isoform Bcl-X(L) which stimulates
CC its GTPase activity in synaptic vesicles; the function may require
CC its recruitment by MFF to clathrin-containing vesicles. Required
CC for programmed necrosis execution.
CC -!- FUNCTION: Isoform 1 and isoform 4 inhibit peroxisomal division
CC when overexpressed.
CC -!- CATALYTIC ACTIVITY: GTP + H(2)O = GDP + phosphate.
CC -!- SUBUNIT: Homotetramer; dimerizes through the N-terminal GTP-middle
CC region of one molecule binding to the GED domain of another DNM1L
CC molecule. Can self-assemble in multimeric ring-like structures.
CC Interacts with GSK3B and MARCH5. Interacts (via the GTPase and B
CC domains) with UBE2I; the interaction promotes sumoylation of
CC DNM1L, mainly in its B domain. Interacts with PPP3CA; the
CC interaction dephosphorylates DNM1L and regulates its transition to
CC mitochondria. Interacts with BCL2L1 isoform BCL-X(L) and CLTA;
CC DNM1L and BCL2L1 isoform BCL-X(L) may form a complex in synaptic
CC vesicles that also contains clathrin and MFF. Interacts with FIS1.
CC Interacts with MIEF2 and MIEF1. Interacts with PGAM5; this
CC interaction leads to dephosphorylation at Ser-656 and activation
CC of GTPase activity and eventually to mitochondria fragmentation.
CC -!- INTERACTION:
CC P03372:ESR1; NbExp=2; IntAct=EBI-724571, EBI-78473;
CC Q5S007:LRRK2; NbExp=8; IntAct=EBI-724571, EBI-5323863;
CC Q9NQG6:MIEF1; NbExp=9; IntAct=EBI-724571, EBI-740987;
CC Q96C03:MIEF2; NbExp=3; IntAct=EBI-724571, EBI-750153;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol. Golgi apparatus.
CC Endomembrane system; Peripheral membrane protein. Mitochondrion
CC outer membrane; Peripheral membrane protein. Peroxisome. Membrane,
CC clathrin-coated pit (By similarity). Cytoplasmic vesicle,
CC secretory vesicle, synaptic vesicle membrane (By similarity).
CC Note=Mainly cytosolic. Translocated to the mitochondrial membrane
CC through O-GlcNAcylation and interaction with FIS1. Colocalized
CC with MARCH5 at mitochondrial membrane. Localizes to mitochondria
CC at sites of division. Localizes to mitochondria following necrosis
CC induction. Associated with peroxisomal membranes, partly recruited
CC there by PEX11B. May also be associated with endoplasmic reticulum
CC tubules and cytoplasmic vesicles and found to be perinuclear. In
CC some cell types, localizes to the Golgi complex.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=1; Synonyms=HdynIV-WT, DLP1F;
CC IsoId=O00429-1; Sequence=Displayed;
CC Name=4; Synonyms=HdynIV-11, DLP1c;
CC IsoId=O00429-2; Sequence=VSP_013688;
CC Name=2; Synonyms=DLP1a;
CC IsoId=O00429-3; Sequence=VSP_013686;
CC Name=3; Synonyms=HdynIV-37, DLP1b;
CC IsoId=O00429-4; Sequence=VSP_013685;
CC Name=5; Synonyms=HdynIV-26;
CC IsoId=O00429-5; Sequence=VSP_013687;
CC Note=No experimental confirmation available;
CC Name=6;
CC IsoId=O00429-6; Sequence=VSP_039097;
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed with highest levels
CC found in skeletal muscles, heart, kidney and brain. Isoform 1 is
CC brain-specific. Isoform 2 and isoform 3 are predominantly
CC expressed in testis and skeletal muscles respectively. Isoform 4
CC is weakly expressed in brain, heart and kidney. Isoform 5 is
CC dominantly expressed in liver, heart and kidney. Isoform 6 is
CC expressed in neurons.
CC -!- DOMAIN: The GED domain folds back to interact, in cis, with the
CC GTP-binding domain and middle domain, and interacts, in trans,
CC with the GED domains of other DNM1L molecules, and is thus
CC critical for activating GTPase activity and for DNM1L
CC dimerization.
CC -!- PTM: Phosphorylation/dephosphorylation events on two sites near
CC the GED domain regulate mitochondrial fission. Phosphorylation on
CC Ser-637 inhibits mitochondrial fission probably through preventing
CC intramolecular interaction. Dephosphorylated on this site by
CC PPP3CA which promotes mitochondrial fission. Phosphorylation on
CC Ser-616 also promotes mitochondrial fission.
CC -!- PTM: Sumoylated on various lysine residues within the B domain,
CC probably by MUL1. Sumoylation positively regulates mitochondrial
CC fission. Desumoylated by SENP5 during G2/M transition of mitosis.
CC Appears to be linked to its catalytic activity.
CC -!- PTM: S-nitrosylation increases DNM1L dimerization, mitochondrial
CC fission and causes neuronal damage.
CC -!- PTM: Ubiquitination by MARCH5 affects mitochondrial morphology.
CC -!- PTM: O-GlcNAcylation augments the level of the GTP-bound active
CC form of DRP1 and induces translocation from the cytoplasm to
CC mitochondria in cardiomyocytes. It also decreases phosphorylation
CC at Ser-637 (By similarity).
CC -!- DISEASE: Note=May be associated with Alzheimer disease through
CC beta-amyloid-induced increased S-nitrosylation of DNM1L, which
CC triggers, directly or indirectly, excessive mitochondrial fission,
CC synaptic loss and neuronal damage.
CC -!- DISEASE: Encephalopathy, lethal, due to defective mitochondrial
CC and peroxisomal fission (EMPF) [MIM:614388]: A rare autosomal
CC dominant systemic disorder resulting in lack of neurologic
CC development and death in infancy. After birth, infants present in
CC the first week of life with poor feeding and neurologic
CC impairment, including hypotonia, little spontaneous movement, no
CC tendon reflexes, no response to light stimulation, and poor visual
CC fixation. Other features include mildly elevated plasma
CC concentration of very-long-chain fatty acids, lactic acidosis,
CC microcephaly, deep-set eyes, optic atrophy and hypoplasia, and an
CC abnormal gyral pattern in both frontal lobes associated with
CC dysmyelination. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the dynamin family.
CC -!- SIMILARITY: Contains 1 GED domain.
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DR EMBL; AB006965; BAA22193.1; -; mRNA.
DR EMBL; AF061795; AAC35283.1; -; mRNA.
DR EMBL; AF000430; AAC23724.1; -; mRNA.
DR EMBL; AF151685; AAD39541.1; -; mRNA.
DR EMBL; AK299926; BAG61760.1; -; mRNA.
DR EMBL; AK291094; BAF83783.1; -; mRNA.
DR EMBL; AC084824; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC087588; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC024590; AAH24590.1; -; mRNA.
DR PIR; JC5695; JC5695.
DR RefSeq; NP_001265392.1; NM_001278463.1.
DR RefSeq; NP_001265393.1; NM_001278464.1.
DR RefSeq; NP_005681.2; NM_005690.4.
DR RefSeq; NP_036192.2; NM_012062.4.
DR RefSeq; NP_036193.2; NM_012063.3.
DR UniGene; Hs.556296; -.
DR PDB; 4BEJ; X-ray; 3.48 A; A/B/C/D=1-736.
DR PDB; 4H1U; X-ray; 2.30 A; A=711-736.
DR PDB; 4H1V; X-ray; 2.30 A; A=2-327.
DR PDBsum; 4BEJ; -.
DR PDBsum; 4H1U; -.
DR PDBsum; 4H1V; -.
DR ProteinModelPortal; O00429; -.
DR SMR; O00429; 1-504, 642-729.
DR IntAct; O00429; 12.
DR MINT; MINT-1394198; -.
DR STRING; 9606.ENSP00000266481; -.
DR PhosphoSite; O00429; -.
DR PaxDb; O00429; -.
DR PRIDE; O00429; -.
DR DNASU; 10059; -.
DR Ensembl; ENST00000266481; ENSP00000266481; ENSG00000087470.
DR Ensembl; ENST00000452533; ENSP00000415131; ENSG00000087470.
DR Ensembl; ENST00000547312; ENSP00000448610; ENSG00000087470.
DR Ensembl; ENST00000549701; ENSP00000450399; ENSG00000087470.
DR Ensembl; ENST00000553257; ENSP00000449089; ENSG00000087470.
DR GeneID; 10059; -.
DR KEGG; hsa:10059; -.
DR UCSC; uc001rld.2; human.
DR CTD; 10059; -.
DR GeneCards; GC12P032832; -.
DR H-InvDB; HIX0010537; -.
DR HGNC; HGNC:2973; DNM1L.
DR HPA; CAB009952; -.
DR MIM; 603850; gene.
DR MIM; 614388; phenotype.
DR neXtProt; NX_O00429; -.
DR Orphanet; 330050; Lethal encephalopathy due to mitochondrial and peroxisomal fission defect.
DR PharmGKB; PA27441; -.
DR eggNOG; COG0699; -.
DR HOVERGEN; HBG107833; -.
DR KO; K17065; -.
DR OMA; RDKSYKV; -.
DR OrthoDB; EOG7GJ6CB; -.
DR PhylomeDB; O00429; -.
DR Reactome; REACT_578; Apoptosis.
DR ChiTaRS; DNM1L; human.
DR GeneWiki; DNM1L; -.
DR GenomeRNAi; 10059; -.
DR NextBio; 38007; -.
DR PMAP-CutDB; O00429; -.
DR PRO; PR:O00429; -.
DR ArrayExpress; O00429; -.
DR Bgee; O00429; -.
DR CleanEx; HS_DNM1L; -.
DR Genevestigator; O00429; -.
DR GO; GO:0030054; C:cell junction; IEA:UniProtKB-KW.
DR GO; GO:0005905; C:coated pit; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
DR GO; GO:0005874; C:microtubule; IDA:UniProtKB.
DR GO; GO:0005741; C:mitochondrial outer membrane; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0005777; C:peroxisome; IDA:UniProtKB.
DR GO; GO:0043234; C:protein complex; IDA:UniProtKB.
DR GO; GO:0030672; C:synaptic vesicle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW.
DR GO; GO:0003924; F:GTPase activity; IDA:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0006921; P:cellular component disassembly involved in execution phase of apoptosis; TAS:Reactome.
DR GO; GO:0003374; P:dynamin polymerization involved in mitochondrial fission; IDA:UniProtKB.
DR GO; GO:0006897; P:endocytosis; IEA:UniProtKB-KW.
DR GO; GO:0090149; P:membrane fission involved in mitochondrial fission; IDA:UniProtKB.
DR GO; GO:0043653; P:mitochondrial fragmentation involved in apoptotic process; IMP:UniProtKB.
DR GO; GO:0070584; P:mitochondrion morphogenesis; IMP:MGI.
DR GO; GO:0070266; P:necroptotic process; IMP:UniProtKB.
DR GO; GO:0016559; P:peroxisome fission; IDA:UniProtKB.
DR GO; GO:2001244; P:positive regulation of intrinsic apoptotic signaling pathway; IMP:UniProtKB.
DR GO; GO:0090141; P:positive regulation of mitochondrial fission; TAS:BHF-UCL.
DR GO; GO:0050714; P:positive regulation of protein secretion; IDA:UniProtKB.
DR GO; GO:0090200; P:positive regulation of release of cytochrome c from mitochondria; IMP:UniProtKB.
DR GO; GO:0051289; P:protein homotetramerization; IDA:UniProtKB.
DR GO; GO:1900063; P:regulation of peroxisome organization; IMP:UniProtKB.
DR InterPro; IPR000375; Dynamin_central.
DR InterPro; IPR001401; Dynamin_GTPase.
DR InterPro; IPR019762; Dynamin_GTPase_CS.
DR InterPro; IPR022812; Dynamin_SF.
DR InterPro; IPR003130; GED.
DR InterPro; IPR020850; GTPase_effector_domain_GED.
DR InterPro; IPR027417; P-loop_NTPase.
DR PANTHER; PTHR11566; PTHR11566; 1.
DR Pfam; PF01031; Dynamin_M; 1.
DR Pfam; PF00350; Dynamin_N; 1.
DR Pfam; PF02212; GED; 1.
DR PRINTS; PR00195; DYNAMIN.
DR SMART; SM00053; DYNc; 1.
DR SMART; SM00302; GED; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR PROSITE; PS00410; DYNAMIN; 1.
DR PROSITE; PS51388; GED; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Cell junction;
KW Coated pit; Complete proteome; Cytoplasm; Cytoplasmic vesicle;
KW Disease mutation; Endocytosis; Glycoprotein; Golgi apparatus;
KW GTP-binding; Hydrolase; Isopeptide bond; Membrane; Mitochondrion;
KW Mitochondrion outer membrane; Necrosis; Nucleotide-binding;
KW Peroxisome; Phosphoprotein; Polymorphism; Reference proteome;
KW S-nitrosylation; Synapse; Ubl conjugation.
FT CHAIN 1 736 Dynamin-1-like protein.
FT /FTId=PRO_0000206566.
FT DOMAIN 644 735 GED.
FT NP_BIND 32 39 GTP (By similarity).
FT NP_BIND 146 150 GTP (By similarity).
FT NP_BIND 215 218 GTP (By similarity).
FT REGION 1 343 GTPase domain.
FT REGION 344 489 Middle domain.
FT REGION 448 685 Interaction with GSK3B.
FT REGION 502 569 B domain.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 548 548 Phosphoserine.
FT MOD_RES 607 607 Phosphoserine.
FT MOD_RES 616 616 Phosphoserine; by CDK1.
FT MOD_RES 637 637 Phosphoserine; by CAMK1 and PKA.
FT MOD_RES 644 644 S-nitrosocysteine.
FT CARBOHYD 585 585 O-linked (GlcNAc) (By similarity).
FT CARBOHYD 586 586 O-linked (GlcNAc) (By similarity).
FT CROSSLNK 532 532 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO).
FT CROSSLNK 535 535 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO).
FT CROSSLNK 558 558 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO).
FT CROSSLNK 568 568 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO).
FT CROSSLNK 594 594 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO)
FT (Probable).
FT CROSSLNK 597 597 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO).
FT CROSSLNK 606 606 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO)
FT (Probable).
FT CROSSLNK 608 608 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO).
FT VAR_SEQ 83 83 N -> NDPATWKNSRHLSK (in isoform 6).
FT /FTId=VSP_039097.
FT VAR_SEQ 533 569 Missing (in isoform 3).
FT /FTId=VSP_013685.
FT VAR_SEQ 533 558 Missing (in isoform 2).
FT /FTId=VSP_013686.
FT VAR_SEQ 544 569 Missing (in isoform 5).
FT /FTId=VSP_013687.
FT VAR_SEQ 559 569 Missing (in isoform 4).
FT /FTId=VSP_013688.
FT VARIANT 71 71 S -> T (in dbSNP:rs1064610).
FT /FTId=VAR_022446.
FT VARIANT 395 395 A -> D (in EMPF; the mutation acts in a
FT dominant-negative manner; defects
FT observed in both mitochondrial and
FT peroxisomal fission).
FT /FTId=VAR_063704.
FT VARIANT 426 426 E -> D (in dbSNP:rs2389105).
FT /FTId=VAR_030489.
FT MUTAGEN 38 38 K->A: Loss of GTPase activity. Impairs
FT mitochondrial division and induces
FT changes in peroxisome morphology. No
FT effect on oligomerization. Increase in
FT sumoylation by SUMO3.
FT MUTAGEN 38 38 K->E: Overexpression delays protein
FT secretion.
FT MUTAGEN 39 39 S->I: Decreased localization to the
FT perinuclear region.
FT MUTAGEN 39 39 S->N: Reduces peroxisomal abundance.
FT MUTAGEN 41 41 V->F: Temperature-sensitive. Impairs
FT mitochondrial division.
FT MUTAGEN 59 59 T->A: Impairs mitochondrial division.
FT Reduces peroxisomal abundance.
FT MUTAGEN 281 281 G->D: Temperature-sensitive. Impairs
FT mitochondrial division.
FT MUTAGEN 300 300 C->A: No effect on S-nitrosylation.
FT MUTAGEN 345 345 C->A: No effect on S-nitrosylation.
FT MUTAGEN 361 361 C->A: No effect on S-nitrosylation.
FT MUTAGEN 367 367 C->A: No effect on S-nitrosylation.
FT MUTAGEN 431 431 C->A: No effect on S-nitrosylation.
FT MUTAGEN 446 446 C->A: No effect on S-nitrosylation.
FT MUTAGEN 470 470 C->A: No effect on S-nitrosylation.
FT MUTAGEN 505 505 C->A: No effect on S-nitrosylation.
FT MUTAGEN 532 532 K->R: Some loss of sumoylation in B
FT domain. Complete loss of sumoylation in B
FT domain; when associated with R-535; R-558
FT and R-568.
FT MUTAGEN 535 535 K->R: Some loss of sumoylation in B
FT domain. Complete loss of sumoylation in B
FT domain; when associated with R-532; R-558
FT and R-568.
FT MUTAGEN 558 558 K->R: Some loss of sumoylation in B
FT domain. Complete loss of sumoylation in B
FT domain; when associated with R-532; R-535
FT and R-568.
FT MUTAGEN 568 568 K->R: Some loss of sumoylation in B
FT domain. Complete loss of sumoylation in B
FT domain; when associated with R-532; R-535
FT and R-558.
FT MUTAGEN 594 594 K->R: Some loss of sumoylation in the GED
FT domain; Complete loss of sumoylation in
FT the GED domain; when associated with R-
FT 597; R-606 and R-608.
FT MUTAGEN 597 597 K->R: Some loss of sumoylation in the GED
FT domain; Complete loss of sumoylation in
FT the GED domain; when associated with R-
FT 594; R-606 and R-608.
FT MUTAGEN 606 606 K->R: Some loss of sumoylation in the GED
FT domain; Complete loss of sumoylation in
FT the GED domain; when associated with R-
FT 594; R-597 and R-608.
FT MUTAGEN 608 608 K->R: Some loss of sumoylation in the GED
FT domain; Complete loss of sumoylation in
FT the GED domain; when associated with R-
FT 594; R-597 and R-606.
FT MUTAGEN 616 616 S->A: Little effect on mitochondrial
FT morphology. Translocated to mitochondria.
FT MUTAGEN 637 637 S->A: Abolishes phosphorylation. Reduces
FT interaction with MIEF1 and MIEF2.
FT Promotes mitochondrial fission and cell
FT vulnerability to apoptotic insults.
FT Mostly mitochondrial. Disrupts, in vitro,
FT binding to FIS1.
FT MUTAGEN 637 637 S->D: Impairs intramolecular, but not
FT intermolecular interactions. Slight
FT reduction in GTPase activity. Does not
FT reduce interaction with MIEF1 and MIEF2.
FT Inhibits mitochondrial fission. Retained
FT in cytoplasm.
FT MUTAGEN 644 644 C->A: Abolishes S-nitrosylation. Reduced
FT dimerization and no enhancement of GTPase
FT activity.
FT MUTAGEN 679 679 K->A: Diminishes intermolecular
FT interaction between GTP-middle domain and
FT GED domain but no effect on
FT oligomerization. Marked reduction in
FT GTPase activity, in vitro. Decreased
FT mitochondrial division.
FT CONFLICT 208 208 R -> C (in Ref. 2; AAC35283 and 4;
FT AAD39541).
FT HELIX 5 14
FT TURN 15 18
FT TURN 21 23
FT STRAND 27 33
FT HELIX 34 36
FT HELIX 38 46
FT STRAND 55 57
FT STRAND 63 69
FT STRAND 86 88
FT STRAND 90 94
FT TURN 95 98
FT HELIX 104 112
FT STRAND 115 117
FT STRAND 120 124
FT STRAND 130 136
FT STRAND 141 146
FT HELIX 155 157
FT HELIX 163 174
FT STRAND 179 186
FT HELIX 191 193
FT HELIX 195 200
FT TURN 201 203
FT STRAND 205 207
FT STRAND 210 215
FT HELIX 217 219
FT STRAND 222 225
FT HELIX 227 230
FT STRAND 233 235
FT STRAND 237 239
FT STRAND 241 243
FT HELIX 249 253
FT HELIX 258 272
FT TURN 274 276
FT HELIX 277 279
FT HELIX 282 322
FT HELIX 329 349
FT HELIX 363 371
FT HELIX 373 380
FT HELIX 389 399
FT HELIX 409 420
FT HELIX 421 424
FT HELIX 425 440
FT TURN 441 443
FT HELIX 444 446
FT HELIX 458 493
FT HELIX 501 504
FT HELIX 632 662
FT HELIX 664 679
FT HELIX 682 688
FT HELIX 711 728
SQ SEQUENCE 736 AA; 81877 MW; F9521A376B785B71 CRC64;
MEALIPVINK LQDVFNTVGA DIIQLPQIVV VGTQSSGKSS VLESLVGRDL LPRGTGIVTR
RPLILQLVHV SQEDKRKTTG EENGVEAEEW GKFLHTKNKL YTDFDEIRQE IENETERISG
NNKGVSPEPI HLKIFSPNVV NLTLVDLPGM TKVPVGDQPK DIELQIRELI LRFISNPNSI
ILAVTAANTD MATSEALKIS REVDPDGRRT LAVITKLDLM DAGTDAMDVL MGRVIPVKLG
IIGVVNRSQL DINNKKSVTD SIRDEYAFLQ KKYPSLANRN GTKYLARTLN RLLMHHIRDC
LPELKTRINV LAAQYQSLLN SYGEPVDDKS ATLLQLITKF ATEYCNTIEG TAKYIETSEL
CGGARICYIF HETFGRTLES VDPLGGLNTI DILTAIRNAT GPRPALFVPE VSFELLVKRQ
IKRLEEPSLR CVELVHEEMQ RIIQHCSNYS TQELLRFPKL HDAIVEVVTC LLRKRLPVTN
EMVHNLVAIE LAYINTKHPD FADACGLMNN NIEEQRRNRL ARELPSAVSR DKSSKVPSAL
APASQEPSPA ASAEADGKLI QDSRRETKNV ASGGGGVGDG VQEPTTGNWR GMLKTSKAEE
LLAEEKSKPI PIMPASPQKG HAVNLLDVPV PVARKLSARE QRDCEVIERL IKSYFLIVRK
NIQDSVPKAV MHFLVNHVKD TLQSELVGQL YKSSLLDDLL TESEDMAQRR KEAADMLKAL
QGASQIIAEI RETHLW
//
MIM
603850
*RECORD*
*FIELD* NO
603850
*FIELD* TI
*603850 DYNAMIN 1-LIKE; DNM1L
;;DYNAMIN-LIKE PROTEIN 1; DLP1;;
DYNAMIN-RELATED PROTEIN 1; DRP1;;
read moreS. CEREVISIAE DNM1/VPS1-LIKE PROTEIN; DVLP;;
DYNAMIN FAMILY MEMBER, PROLINE-RICH C-TERMINAL DOMAIN-LESS; DYMPLE
*FIELD* TX
DESCRIPTION
DNM1L belongs to the dynamin (see DNM1; 602377) family of large GTPases
that mediate membrane remodeling during a variety of cellular processes.
DNM1L has an important role in the division of growing mitochondria and
peroxisomes (summary by Pitts et al. (2004)).
CLONING
By PCR amplification of human hepatoma HepG2 cDNA using oligonucleotides
based on human ESTs homologous to Vps1 and Dnm1 (602377), Shin et al.
(1997) obtained a partial cDNA which they used to screen a HepG2 cDNA
library. They isolated cDNAs encoding a predicted 736-amino acid
protein, DNM1L, which they designated DVLP. DVLP contains the highly
conserved N-terminal tripartite GTP-binding domain, but it lacks the
pleckstrin homology domain and proline-rich region. It shares 45% and
42% amino acid identity with yeast Dnm1 and Vps1, respectively.
Immunofluorescence studies of mammalian cells showed that DVLP localized
to the perinuclear region and did not colocalize with endoplasmic
reticulum (ER) or Golgi marker proteins.
By searching an EST database with a rat dynamin-3 (see 611445) amino
acid sequence, Imoto et al. (1998) identified a human cDNA encoding
DNM1L, which they called DRP1. Northern blot analysis indicated that
DRP1 was expressed ubiquitously in human tissues, with highest levels in
skeletal muscle, heart, kidney, and brain. Immunolocalization studies
showed that DRP1 was enriched in a perinuclear compartment that labeled
with ER and Golgi markers. The localization of DRP1 was highly similar
to the localization of the ER and cis-Golgi GTPase RAB1 (179508), but
not to the localization of the trans-Golgi GTPase RAB6 (179513).
By immunoscreening a HeLa cell cDNA expression library with serum from a
scleroderma (181750) patient, Kamimoto et al. (1998) isolated cDNAs
encoding DNM1L, which they referred to as DYMPLE. They identified cDNAs
corresponding to 3 alternatively spliced DYMPLE transcripts, which
encode a deduced 736-amino acid protein and deduced isoforms containing
a 29- or 37-amino acid deletion in the C-terminal region. RT-PCR
analysis of mouse tissues demonstrated that alternative splicing
occurred in a tissue-specific manner. Northern blot analysis detected
2.5- and 4.2-kb DYMPLE transcripts in all human tissues examined. The
authors reported that these transcripts were alternatively
polyadenylated. In situ hybridization analysis of mouse brain showed
abundant expression of Dymple mRNA in the cerebellum and in several
regions of the cerebrum and diencephalon. High levels of Dymple mRNA
were found in cerebellar Purkinje cells and pontile giant neurons.
Using a yeast 2-hybrid system to identify proteins that interact with
glycogen synthase kinase-3-beta (GSK3B; 605004), Hong et al. (1998)
isolated a human fetal liver cDNA encoding DNM1L, which they called
dynamin-like protein-4 (DYNIV). The deduced protein contains 699 amino
acids.
Howng et al. (2004) identified 4 DYNIV splice variants that encode the
full-length 736-amino acid protein and 699-, 710-, and 725-amino acid
isoforms. All isoforms contain an N-terminal tripartite
GTPase/GTP-binding site, and the shorter isoforms bear various in-frame
deletions in their C-terminal halves relative to full-length DYNIV.
RT-PCR detected variable expression of all 4 splice variants in 6 human
cell lines examined.
Pitts et al. (2004) noted that DLP1 has a dynamin-like protein
structure, with a conserved N-terminal GTPase domain, followed by a
conserved middle domain, a nonconserved region, and a conserved
C-terminal coiled-coil domain. Yoon (2010) stated that there are 12
splice variants of rat Dlp1 that encode proteins of 705 to 761 amino
acids. The differential splicing results in changes within the GTPase
and nonconserved domains.
GENE FAMILY
The dynamin superfamily of GTPases is divided into subfamilies on the
basis of structural similarity. Members of the dynamin subfamily,
including dynamin-1 (DNM1; 602377), dynamin-2 (DNM2; 602378), and
dynamin-3 (DNM3; 611445), contain an N-terminal tripartite GTPase
domain, a pleckstrin homology domain, and a C-terminal proline-rich
region. Dynamin subfamily members have been shown to participate in
clathrin-mediated endocytosis at the plasma membrane. Members of the
dynamin-related subfamily, including the S. cerevisiae proteins Dnm1 and
Vps1, contain the N-terminal tripartite GTPase domain but do not have
the pleckstrin homology or proline-rich domains. Vps1 has been shown to
play a role in vesicular transport from the late Golgi compartment to
vacuoles, and Dnm1 is thought to be involved in endosomal trafficking.
Furthermore, Dnm1 has been shown to be essential for the maintenance of
mitochondrial morphology (Otsuga et al., 1998). Mitochondria exist as a
dynamic tubular network with projections that move, break, and reseal in
response to local environmental changes. Dnm1 is required for the
cortical distribution of this network.
GENE FUNCTION
To determine the function of DRP1 (DNM1L), Smirnova et al. (1998)
expressed mutant DRP1 in COS-7 cells. A mutation in the GTPase domain
caused profound alterations in mitochondrial morphology. In cells
expressing mutant DRP1, the tubular projections normally present in
wildtype cells were retracted into large perinuclear aggregates. By
electron microscopy, the mitochondrial aggregates appeared as clusters
of tubules rather than as a large mass of coalescing membrane. The
morphology of other organelles was unaffected by mutant DRP1. In
addition, mutant DRP1 had no effect on the transport functions of the
secretory and endocytic pathways. The authors proposed that DRP1
establishes mitochondrial morphology through a role in distributing
mitochondrial tubules throughout the cytoplasm. They suggested that DRP1
is the functional equivalent of yeast Dnm1.
Imoto et al. (1998) demonstrated that overexpression of wildtype human
DRP1 in mammalian cells increased secretion of a luciferase reporter
protein, whereas overexpression of a GTP-binding site mutant of DRP1
decreased secretion of this marker.
Using an in vitro GTPase assay, Kamimoto et al. (1998) showed that a
bacterially expressed DYMPLE fusion protein hydrolyzed GTP without
additive modifications or coactivators.
Hong et al. (1998) showed that the C-terminal region of the 699-amino
acid DYNIV protein bound to GSK3B.
Shin et al. (1999) found that DNM1L was oligomeric, probably tetrameric,
under physiologic salt conditions, and that it aggregated into
sedimentable complexes under low salt conditions. Analyses using the
yeast 2-hybrid system and immunoprecipitation showed that the N-terminal
and C-terminal regions of DNM1L could interact with each other.
Pitts et al. (1999) transiently transfected normal rat liver cells with
wildtype rat Dlp1 and Dlp1 containing point mutations within conserved
GTP-binding domains. Wildtype Dlp1 localized to distinct nonrandom foci
along the length of mitochondria and in linear arrays on microtubules
and the ER. Expression of the mutant proteins caused a pronounced
collapse of mitochondria into the cell center. The ER of cells
expressing mutant Dlp1 was also less distinct and appeared vesiculated.
Unlike the diffuse cytoplasmic distribution of wildtype DRP1, Santel and
Fuller (2001) found that a GTPase-dead DRP1 mutant distributed to
punctate structures in transfected COS-7 cells. In addition,
mitochondria formed perinuclear aggregates similar to the aggregates
formed in cells overexpressing mitofusin-2 (MFN2; 608507). COS-7 cells
cotransfected with the GTPase-dead DRP1 and MFN2 developed mitochondrial
tubules that extended from the perinuclear mitochondrial cluster towards
the cell periphery. Santel and Fuller (2001) concluded that the size and
morphologic arrangement of mitochondria are due to a dynamic balance
between MFN-dependent mitochondrial fusion and DRP1-dependent
mitochondrial fission.
Yoon et al. (2003) observed that human FIS1 (609003) and rat Dlp1 formed
a complex in transfected cells and could interact with each other
directly in vitro. These and other findings provided evidence that FIS1
regulates mitochondrial fission through a protein-protein interaction
that recruits DLP1 from the cytosol to the mitochondrial surface.
Li and Gould (2003) showed that overexpression of PEX11-beta (PEX11B;
603867) in human fibroblasts induced peroxisome division in a multistep
process involving elongation of preexisting peroxisomes followed by
their division. They found that DLP1 was essential for the peroxisome
division. The 710-amino acid DLP1 isoform, DLP1a, associated with
peroxisomes, and PEX11-beta overexpression recruited DLP1a to peroxisome
membranes. DLP1a and PEX11 proteins did not appear to interact directly.
By swapping domains between rat Dnm2 and rat Dlp1, Pitts et al. (2004)
showed that the coiled-coil domain of Dlp1 conferred mitochondrial
targeting to the protein. However, the mitochondria-specific function of
Dlp1 also required the middle and nonconserved domains.
Jagasia et al. (2005) showed that Drp1, a key component of the
mitochondrial fission machinery, was required and sufficient to induce
mitochondrial fragmentation and programmed cell death during C. elegans
development.
Germain et al. (2005) found that fluorescence-tagged rodent Drp1 was
expressed in the cytosol of COS-7 cells, and that treatment of COS-7 and
human cells with the apoptotic protein BIK (603392) resulted in
recruitment of Drp1 to mitochondria prior to mitochondrial
fragmentation. Drp1 maintained association with mitochondria during
their initial shape change and following loss of mitochondrial potential
and mobilization of cytochrome c (123970). Transmission electron
microscopy showed that BIK expression caused profound opening of
mitochondrial cristae, and these changes were inhibited by expression of
a dominant-negative Drp1 mutant. Germain et al. (2005) concluded that
DRP1 is involved in remodeling and opening of mitochondrial cristae
during apoptosis, and that this function of DRP1 is distinct from its
role in mitochondrial fission.
Type III, or necrosis-like, programmed cell death (PCD) is defined
exclusively by cytoplasmic features and seems to operate in a
caspase-independent manner. Bras et al. (2007) showed that ligation of
CD47 (601028) triggered type III PCD in B cells from healthy volunteers
and patients with chronic lymphocytic leukemia (CLL; 151400), and they
identified DRP1 as a key mediator of this PCD. CD47 ligation induced
DRP1 translocation from the cytosol to mitochondria. In mitochondria,
DRP1 provoked impairment of the mitochondrial electron transport chain,
resulting in dissipation of mitochondrial transmembrane potential,
generation of reactive oxygen species, and a drop in ATP levels.
Responsiveness of cells to CD47 ligation increased following DRP1
overexpression, while resistance to CD47-mediated death was observed
following DRP1 downregulation. In CLL B cells, DRP1 mRNA levels strongly
correlated with death sensitivity.
Cho et al. (2009) found that nitric oxide produced in response to
beta-amyloid protein (104760), thought to be a key mediator of Alzheimer
disease (see 104300), triggered mitochondrial fission, synaptic loss,
and neuronal damage, in part via S-nitrosylation of DRP1 (forming
SNO-DRP1). Preventing nitrosylation of DRP1 by cysteine mutation
abrogated these neurotoxic events. Cho et al. (2009) showed that
SNO-DRP1 is increased in brains of human Alzheimer disease patients and
may thus contribute to the pathogenesis of neurodegeneration.
Malena et al. (2009) tested the hypothesis that altering the balance
between mitochondrial fusion and fission could influence the segregation
of mutant and wildtype mtDNA variants, because it would modify the
number of organelles per cell. Human cells heteroplasmic for the
pathologic 3243A-G (MTTL1; 590050.0001) mitochondrial DNA mutation were
transfected with constructs designed to silence DRP1 or human FIS1
(TTC11; 609003), whose gene products are required for mitochondrial
fission. DRP1 and FIS1 gene silencing were both associated with
increased levels of mutant mitochondrial DNA. The authors concluded that
the extent of the mitochondrial reticular network appears to be an
important factor in determining mutant load.
Huntington disease (HD; 143100) is a neurodegenerative disorder caused
by abnormal expansion of a polyglutamine (polyQ) tract in huntingtin
(HTT; 613004). Song et al. (2011) found mitochondrial abnormalities,
including fragmentation, altered cristae morphology, and arrested
intracellular movement, in fibroblasts from a patient with HD and in
neurons of rodent models of HD. Immunoprecipitation of normal and HD
human or mouse brain indicated that mutant, but not normal, huntingtin
interacted with Drp1. In vitro assays with liposomes that mimicked the
mitochondrial outer membrane revealed that mutant huntingtin stimulated
Drp1 GTPase activity. Expression of a dominant-negative Drp1 mutant
rescued mutant huntingtin-mediated mitochondrial fragmentation, defects
in mitochondrial transport, and neuronal cell death. Electron microscopy
showed that the normal ring- and spiral-like organization of DRP1
oligomers had an additional layer of density with the addition of
mutant, but not normal, huntingtin.
Using Western blot analysis, Wang et al. (2011) found that the
phosphorylated form of Drp1 accumulated in the cytosol of control
neonatal rat cardiomyocytes, whereas the unphosphorylated form of Drp1
accumulated in mitochondria-enriched fractions following anoxia
treatment. Drp1 translocation to mitochondria was associated with
anoxia-induced mitochondrial fragmentation and apoptosis. Wang et al.
(2011) characterized upstream events in this apoptotic pathway and found
that p53 (TP53; 191170) downregulated expression of microRNA-499
(MIR499; 613614), which relieved Mir499-dependent repression of the
calcineurin catalytic subunits Cna-alpha (PPP3CA; 114105) and Cna-beta
(PPP3CB; 114106). Knockdown of either Cna-alpha or Cna-beta via small
interfering RNA attenuated dephosphorylation-dependent Drp1 accumulation
in mitochondria, mitochondria fragmentation, and anoxia-induced cell
death.
Endoplasmic reticulum and mitochondria exhibit tightly coupled dynamics
and have extensive contacts. In yeast and mammalian cells, Friedman et
al. (2011) tested whether endoplasmic reticulum plays a role in
mitochondrial division. They found that mitochondrial division occurred
at positions where endoplasmic reticulum tubules contacted mitochondria
and mediated constriction before Drp1 recruitment. Friedman et al.
(2011) concluded that endoplasmic reticulum may play an active role in
defining the position of mitochondrial division sites.
Wang et al. (2012) found that RIP1 (RIPK1; 603453), RIP3 (RIPK3;
605817), and MLKL (615153) formed a necrosis complex in human cell
lines. Upon induction of necrosis by TNF-alpha (191160), both isoforms
of PGAM5 (614939), PGAM5L and PGAM5S, interacted with the RIP1-RIP3-MLKL
necrosis complex and were phosphorylated. Phosphorylated PGAM5S then
recruited DRP1 and activated DRP1 by dephosphorylation, resulting in
mitochondrial fragmentation and execution of necrosis. Blockade of
phosphorylation or dephosphorylation signaling at several points in this
signaling cascade, or knockdown of PGAM5 expression, blocked
TNF-alpha-induced necrosis. Knockdown experiments showed that both PGAM5
isoforms and DRP1, but not RIP1, RIP3, or MLKL, were also involved in
necrosis induced by reactive oxygen species or ionophore-mediated
calcium shock.
Korobova et al. (2013) found that actin polymerization through
endoplasmic reticulum (ER)-localized inverted formin-2 (INF2; 610982)
was required for efficient mitochondrial fission in mammalian cells.
INF2 functioned upstream of DRP1. Actin filaments appeared to accumulate
between mitochondria and INF2-enriched ER membranes at constriction
sites. Thus, INF2-induced actin filaments may drive initial
mitochondrial constriction, which allows DRP1-driven secondary
constriction.
GENE STRUCTURE
Howng et al. (2004) determined that the DNM1L gene contains 20 exons and
spans 64 kb. Exons 15 and 16 are subject to differential splicing. The
5-prime flanking sequence contains 3 GC boxes that concatenate AP2
(TFAP2A; 107580)- and SP1 (189906)-binding motifs, but it lacks TATA or
CAAT consensus sequences. Deletion analysis located the minimal promoter
at nucleotides -108 to -100.
MAPPING
By genomic sequence analysis, Howng et al. (2004) mapped the DNM1L gene
to chromosome 12.
MOLECULAR GENETICS
In a newborn girl with a lethal encephalopathy due to defective
mitochondrial and peroxisomal fission (EMPF; 614388), Waterham et al.
(2007) identified a de novo heterozygous dominant-negative mutation in
the dynamin gene DLP1 (A395D; 603850.0001). The affected infant showed
microcephaly, abnormal brain development, optic atrophy and hypoplasia,
persistent lactic acidemia, and a mildly elevated plasma concentration
of very long-chain fatty acids. Magnetic resonance imaging (MRI)
detected an abnormal gyral pattern in both frontal lobes and was
associated with dysmyelination. Death occurred at 37 days of age.
Immunofluorescence microscopic analyses showed fewer peroxisomes in
fibroblasts from the patient of Waterham et al. (2007) than in
fibroblasts from control subjects. Furthermore, the peroxisomes from the
patient varied markedly in size and were frequently arranged in rows.
This arrangement was similar to that seen in mammalian cells
overexpressing dominant-negative mutant DLP1 or those with DLP1
expression that had been downregulated owing to RNA interference (Koch
et al., 2003; Li and Gould, 2003). Because such mammalian cells also
showed a defect in mitochondrial fission (Smirnova et al., 2001; Yoon et
al., 2001), Waterham et al. (2007) studied the mitochondria of
fibroblasts from the patient using a fluorescent mitochondrial probe.
Mitochondria in the patient's fibroblasts were elongated, tangled,
tubular structures concentrated predominantly around the nucleus.
ANIMAL MODEL
Ishihara et al. (2009) found that Drp1 deletion in mice was embryonic
lethal. Drp1 -/- embryos showed reduced development of the heart and
liver, as well as thinned neural tube cell layer. Electron microscopy
revealed that Drp1 -/- embryos had enlarged mitochondria with normal
cristae and cytochrome c oxidase (see 516030) activity. Embryonic
fibroblasts and stem cells from Drp1 -/- mice were healthy and
proliferated normally. The ER and Golgi of Drp1 -/- cells appeared
normal, but their mitochondria were abnormally extended and clustered
near the nucleus. Peroxisomes were also swollen in Drp1 -/- cells.
Cytokinesis in Drp1 -/- fibroblasts proceeded asymmetrically, with
filamentous and highly clustered mitochondria cleaved at a constriction
site of the cell in concert with cytokinesis and segregated unequally
into the daughter cells. Treatment of Drp1 -/- cells with proapoptotic
reagents suggested that Drp1 is involved in later apoptotic events,
including cytochrome c release and caspase activation. Mice with neural
cell-specific Drp1 deletion (NS-Drp1 -/- mice) died shortly after birth
as a result of brain hypoplasia and apoptosis. Primary cultures of
NS-Drp1 -/- mouse forebrain showed decreased number of neurites and
defective synapse formation, suggesting that aggregated mitochondria
fail to distribute properly within neural cell processes. NS-Drp1 -/-
neuronal cells were also highly sensitive to Ca(2+)-dependent apoptosis.
*FIELD* AV
.0001
ENCEPHALOPATHY, LETHAL, DUE TO DEFECTIVE MITOCHONDRIAL AND PEROXISOMAL
FISSION
DNM1L, ALA395ASP
In an infant with a lethal encephalopathy due to defective mitochondrial
and peroxisomal fission (EMPF; 614388), Waterham et al. (2007) found
heterozygosity for a 1184C-A transversion in the DNM1L gene that
resulted in an ala395-to-asp (A395D) substitution in the middle domain
of the protein. The mutation was not found in genomic DNA from blood
cells from either parent, indicating that the mutation either was de
novo or was present only in germline cells of 1 parent. The patient
presented in the first days of life with microcephaly, abnormal brain
development, optic atrophy and hypoplasia, and lactic acidemia, and died
at age 37 days. Overexpression of mutant DNM1L from the patient in
fibroblasts from control subjects induced aberrant mitochondrial and
peroxisomal phenotypes, indicating that the mutation acted in a
dominant-negative manner.
*FIELD* RF
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*FIELD* CN
Ada Hamosh - updated: 2/21/2013
Patricia A. Hartz - updated: 10/26/2012
Ada Hamosh - updated: 1/4/2012
Patricia A. Hartz - updated: 8/25/2011
Patricia A. Hartz - updated: 8/22/2011
George E. Tiller - updated: 7/7/2010
Patricia A. Hartz - updated: 1/19/2010
Ada Hamosh - updated: 6/16/2009
Victor A. McKusick - updated: 11/19/2007
Ada Hamosh - updated: 4/15/2005
Patricia A. Hartz - updated: 2/11/2004
*FIELD* CD
Patti M. Sherman: 5/26/1999
*FIELD* ED
mgross: 03/29/2013
alopez: 2/26/2013
terry: 2/21/2013
carol: 2/6/2013
mgross: 11/16/2012
terry: 10/26/2012
alopez: 1/6/2012
terry: 1/4/2012
carol: 12/12/2011
ckniffin: 12/12/2011
mgross: 8/26/2011
terry: 8/25/2011
mgross: 8/24/2011
terry: 8/22/2011
alopez: 7/20/2010
terry: 7/7/2010
mgross: 1/25/2010
terry: 1/19/2010
alopez: 6/22/2009
terry: 6/16/2009
carol: 10/15/2008
alopez: 11/19/2007
alopez: 4/22/2005
terry: 4/15/2005
mgross: 3/5/2004
cwells: 3/3/2004
terry: 2/11/2004
carol: 5/25/2000
psherman: 4/17/2000
psherman: 5/27/1999
mgross: 5/27/1999
psherman: 5/27/1999
*RECORD*
*FIELD* NO
603850
*FIELD* TI
*603850 DYNAMIN 1-LIKE; DNM1L
;;DYNAMIN-LIKE PROTEIN 1; DLP1;;
DYNAMIN-RELATED PROTEIN 1; DRP1;;
read moreS. CEREVISIAE DNM1/VPS1-LIKE PROTEIN; DVLP;;
DYNAMIN FAMILY MEMBER, PROLINE-RICH C-TERMINAL DOMAIN-LESS; DYMPLE
*FIELD* TX
DESCRIPTION
DNM1L belongs to the dynamin (see DNM1; 602377) family of large GTPases
that mediate membrane remodeling during a variety of cellular processes.
DNM1L has an important role in the division of growing mitochondria and
peroxisomes (summary by Pitts et al. (2004)).
CLONING
By PCR amplification of human hepatoma HepG2 cDNA using oligonucleotides
based on human ESTs homologous to Vps1 and Dnm1 (602377), Shin et al.
(1997) obtained a partial cDNA which they used to screen a HepG2 cDNA
library. They isolated cDNAs encoding a predicted 736-amino acid
protein, DNM1L, which they designated DVLP. DVLP contains the highly
conserved N-terminal tripartite GTP-binding domain, but it lacks the
pleckstrin homology domain and proline-rich region. It shares 45% and
42% amino acid identity with yeast Dnm1 and Vps1, respectively.
Immunofluorescence studies of mammalian cells showed that DVLP localized
to the perinuclear region and did not colocalize with endoplasmic
reticulum (ER) or Golgi marker proteins.
By searching an EST database with a rat dynamin-3 (see 611445) amino
acid sequence, Imoto et al. (1998) identified a human cDNA encoding
DNM1L, which they called DRP1. Northern blot analysis indicated that
DRP1 was expressed ubiquitously in human tissues, with highest levels in
skeletal muscle, heart, kidney, and brain. Immunolocalization studies
showed that DRP1 was enriched in a perinuclear compartment that labeled
with ER and Golgi markers. The localization of DRP1 was highly similar
to the localization of the ER and cis-Golgi GTPase RAB1 (179508), but
not to the localization of the trans-Golgi GTPase RAB6 (179513).
By immunoscreening a HeLa cell cDNA expression library with serum from a
scleroderma (181750) patient, Kamimoto et al. (1998) isolated cDNAs
encoding DNM1L, which they referred to as DYMPLE. They identified cDNAs
corresponding to 3 alternatively spliced DYMPLE transcripts, which
encode a deduced 736-amino acid protein and deduced isoforms containing
a 29- or 37-amino acid deletion in the C-terminal region. RT-PCR
analysis of mouse tissues demonstrated that alternative splicing
occurred in a tissue-specific manner. Northern blot analysis detected
2.5- and 4.2-kb DYMPLE transcripts in all human tissues examined. The
authors reported that these transcripts were alternatively
polyadenylated. In situ hybridization analysis of mouse brain showed
abundant expression of Dymple mRNA in the cerebellum and in several
regions of the cerebrum and diencephalon. High levels of Dymple mRNA
were found in cerebellar Purkinje cells and pontile giant neurons.
Using a yeast 2-hybrid system to identify proteins that interact with
glycogen synthase kinase-3-beta (GSK3B; 605004), Hong et al. (1998)
isolated a human fetal liver cDNA encoding DNM1L, which they called
dynamin-like protein-4 (DYNIV). The deduced protein contains 699 amino
acids.
Howng et al. (2004) identified 4 DYNIV splice variants that encode the
full-length 736-amino acid protein and 699-, 710-, and 725-amino acid
isoforms. All isoforms contain an N-terminal tripartite
GTPase/GTP-binding site, and the shorter isoforms bear various in-frame
deletions in their C-terminal halves relative to full-length DYNIV.
RT-PCR detected variable expression of all 4 splice variants in 6 human
cell lines examined.
Pitts et al. (2004) noted that DLP1 has a dynamin-like protein
structure, with a conserved N-terminal GTPase domain, followed by a
conserved middle domain, a nonconserved region, and a conserved
C-terminal coiled-coil domain. Yoon (2010) stated that there are 12
splice variants of rat Dlp1 that encode proteins of 705 to 761 amino
acids. The differential splicing results in changes within the GTPase
and nonconserved domains.
GENE FAMILY
The dynamin superfamily of GTPases is divided into subfamilies on the
basis of structural similarity. Members of the dynamin subfamily,
including dynamin-1 (DNM1; 602377), dynamin-2 (DNM2; 602378), and
dynamin-3 (DNM3; 611445), contain an N-terminal tripartite GTPase
domain, a pleckstrin homology domain, and a C-terminal proline-rich
region. Dynamin subfamily members have been shown to participate in
clathrin-mediated endocytosis at the plasma membrane. Members of the
dynamin-related subfamily, including the S. cerevisiae proteins Dnm1 and
Vps1, contain the N-terminal tripartite GTPase domain but do not have
the pleckstrin homology or proline-rich domains. Vps1 has been shown to
play a role in vesicular transport from the late Golgi compartment to
vacuoles, and Dnm1 is thought to be involved in endosomal trafficking.
Furthermore, Dnm1 has been shown to be essential for the maintenance of
mitochondrial morphology (Otsuga et al., 1998). Mitochondria exist as a
dynamic tubular network with projections that move, break, and reseal in
response to local environmental changes. Dnm1 is required for the
cortical distribution of this network.
GENE FUNCTION
To determine the function of DRP1 (DNM1L), Smirnova et al. (1998)
expressed mutant DRP1 in COS-7 cells. A mutation in the GTPase domain
caused profound alterations in mitochondrial morphology. In cells
expressing mutant DRP1, the tubular projections normally present in
wildtype cells were retracted into large perinuclear aggregates. By
electron microscopy, the mitochondrial aggregates appeared as clusters
of tubules rather than as a large mass of coalescing membrane. The
morphology of other organelles was unaffected by mutant DRP1. In
addition, mutant DRP1 had no effect on the transport functions of the
secretory and endocytic pathways. The authors proposed that DRP1
establishes mitochondrial morphology through a role in distributing
mitochondrial tubules throughout the cytoplasm. They suggested that DRP1
is the functional equivalent of yeast Dnm1.
Imoto et al. (1998) demonstrated that overexpression of wildtype human
DRP1 in mammalian cells increased secretion of a luciferase reporter
protein, whereas overexpression of a GTP-binding site mutant of DRP1
decreased secretion of this marker.
Using an in vitro GTPase assay, Kamimoto et al. (1998) showed that a
bacterially expressed DYMPLE fusion protein hydrolyzed GTP without
additive modifications or coactivators.
Hong et al. (1998) showed that the C-terminal region of the 699-amino
acid DYNIV protein bound to GSK3B.
Shin et al. (1999) found that DNM1L was oligomeric, probably tetrameric,
under physiologic salt conditions, and that it aggregated into
sedimentable complexes under low salt conditions. Analyses using the
yeast 2-hybrid system and immunoprecipitation showed that the N-terminal
and C-terminal regions of DNM1L could interact with each other.
Pitts et al. (1999) transiently transfected normal rat liver cells with
wildtype rat Dlp1 and Dlp1 containing point mutations within conserved
GTP-binding domains. Wildtype Dlp1 localized to distinct nonrandom foci
along the length of mitochondria and in linear arrays on microtubules
and the ER. Expression of the mutant proteins caused a pronounced
collapse of mitochondria into the cell center. The ER of cells
expressing mutant Dlp1 was also less distinct and appeared vesiculated.
Unlike the diffuse cytoplasmic distribution of wildtype DRP1, Santel and
Fuller (2001) found that a GTPase-dead DRP1 mutant distributed to
punctate structures in transfected COS-7 cells. In addition,
mitochondria formed perinuclear aggregates similar to the aggregates
formed in cells overexpressing mitofusin-2 (MFN2; 608507). COS-7 cells
cotransfected with the GTPase-dead DRP1 and MFN2 developed mitochondrial
tubules that extended from the perinuclear mitochondrial cluster towards
the cell periphery. Santel and Fuller (2001) concluded that the size and
morphologic arrangement of mitochondria are due to a dynamic balance
between MFN-dependent mitochondrial fusion and DRP1-dependent
mitochondrial fission.
Yoon et al. (2003) observed that human FIS1 (609003) and rat Dlp1 formed
a complex in transfected cells and could interact with each other
directly in vitro. These and other findings provided evidence that FIS1
regulates mitochondrial fission through a protein-protein interaction
that recruits DLP1 from the cytosol to the mitochondrial surface.
Li and Gould (2003) showed that overexpression of PEX11-beta (PEX11B;
603867) in human fibroblasts induced peroxisome division in a multistep
process involving elongation of preexisting peroxisomes followed by
their division. They found that DLP1 was essential for the peroxisome
division. The 710-amino acid DLP1 isoform, DLP1a, associated with
peroxisomes, and PEX11-beta overexpression recruited DLP1a to peroxisome
membranes. DLP1a and PEX11 proteins did not appear to interact directly.
By swapping domains between rat Dnm2 and rat Dlp1, Pitts et al. (2004)
showed that the coiled-coil domain of Dlp1 conferred mitochondrial
targeting to the protein. However, the mitochondria-specific function of
Dlp1 also required the middle and nonconserved domains.
Jagasia et al. (2005) showed that Drp1, a key component of the
mitochondrial fission machinery, was required and sufficient to induce
mitochondrial fragmentation and programmed cell death during C. elegans
development.
Germain et al. (2005) found that fluorescence-tagged rodent Drp1 was
expressed in the cytosol of COS-7 cells, and that treatment of COS-7 and
human cells with the apoptotic protein BIK (603392) resulted in
recruitment of Drp1 to mitochondria prior to mitochondrial
fragmentation. Drp1 maintained association with mitochondria during
their initial shape change and following loss of mitochondrial potential
and mobilization of cytochrome c (123970). Transmission electron
microscopy showed that BIK expression caused profound opening of
mitochondrial cristae, and these changes were inhibited by expression of
a dominant-negative Drp1 mutant. Germain et al. (2005) concluded that
DRP1 is involved in remodeling and opening of mitochondrial cristae
during apoptosis, and that this function of DRP1 is distinct from its
role in mitochondrial fission.
Type III, or necrosis-like, programmed cell death (PCD) is defined
exclusively by cytoplasmic features and seems to operate in a
caspase-independent manner. Bras et al. (2007) showed that ligation of
CD47 (601028) triggered type III PCD in B cells from healthy volunteers
and patients with chronic lymphocytic leukemia (CLL; 151400), and they
identified DRP1 as a key mediator of this PCD. CD47 ligation induced
DRP1 translocation from the cytosol to mitochondria. In mitochondria,
DRP1 provoked impairment of the mitochondrial electron transport chain,
resulting in dissipation of mitochondrial transmembrane potential,
generation of reactive oxygen species, and a drop in ATP levels.
Responsiveness of cells to CD47 ligation increased following DRP1
overexpression, while resistance to CD47-mediated death was observed
following DRP1 downregulation. In CLL B cells, DRP1 mRNA levels strongly
correlated with death sensitivity.
Cho et al. (2009) found that nitric oxide produced in response to
beta-amyloid protein (104760), thought to be a key mediator of Alzheimer
disease (see 104300), triggered mitochondrial fission, synaptic loss,
and neuronal damage, in part via S-nitrosylation of DRP1 (forming
SNO-DRP1). Preventing nitrosylation of DRP1 by cysteine mutation
abrogated these neurotoxic events. Cho et al. (2009) showed that
SNO-DRP1 is increased in brains of human Alzheimer disease patients and
may thus contribute to the pathogenesis of neurodegeneration.
Malena et al. (2009) tested the hypothesis that altering the balance
between mitochondrial fusion and fission could influence the segregation
of mutant and wildtype mtDNA variants, because it would modify the
number of organelles per cell. Human cells heteroplasmic for the
pathologic 3243A-G (MTTL1; 590050.0001) mitochondrial DNA mutation were
transfected with constructs designed to silence DRP1 or human FIS1
(TTC11; 609003), whose gene products are required for mitochondrial
fission. DRP1 and FIS1 gene silencing were both associated with
increased levels of mutant mitochondrial DNA. The authors concluded that
the extent of the mitochondrial reticular network appears to be an
important factor in determining mutant load.
Huntington disease (HD; 143100) is a neurodegenerative disorder caused
by abnormal expansion of a polyglutamine (polyQ) tract in huntingtin
(HTT; 613004). Song et al. (2011) found mitochondrial abnormalities,
including fragmentation, altered cristae morphology, and arrested
intracellular movement, in fibroblasts from a patient with HD and in
neurons of rodent models of HD. Immunoprecipitation of normal and HD
human or mouse brain indicated that mutant, but not normal, huntingtin
interacted with Drp1. In vitro assays with liposomes that mimicked the
mitochondrial outer membrane revealed that mutant huntingtin stimulated
Drp1 GTPase activity. Expression of a dominant-negative Drp1 mutant
rescued mutant huntingtin-mediated mitochondrial fragmentation, defects
in mitochondrial transport, and neuronal cell death. Electron microscopy
showed that the normal ring- and spiral-like organization of DRP1
oligomers had an additional layer of density with the addition of
mutant, but not normal, huntingtin.
Using Western blot analysis, Wang et al. (2011) found that the
phosphorylated form of Drp1 accumulated in the cytosol of control
neonatal rat cardiomyocytes, whereas the unphosphorylated form of Drp1
accumulated in mitochondria-enriched fractions following anoxia
treatment. Drp1 translocation to mitochondria was associated with
anoxia-induced mitochondrial fragmentation and apoptosis. Wang et al.
(2011) characterized upstream events in this apoptotic pathway and found
that p53 (TP53; 191170) downregulated expression of microRNA-499
(MIR499; 613614), which relieved Mir499-dependent repression of the
calcineurin catalytic subunits Cna-alpha (PPP3CA; 114105) and Cna-beta
(PPP3CB; 114106). Knockdown of either Cna-alpha or Cna-beta via small
interfering RNA attenuated dephosphorylation-dependent Drp1 accumulation
in mitochondria, mitochondria fragmentation, and anoxia-induced cell
death.
Endoplasmic reticulum and mitochondria exhibit tightly coupled dynamics
and have extensive contacts. In yeast and mammalian cells, Friedman et
al. (2011) tested whether endoplasmic reticulum plays a role in
mitochondrial division. They found that mitochondrial division occurred
at positions where endoplasmic reticulum tubules contacted mitochondria
and mediated constriction before Drp1 recruitment. Friedman et al.
(2011) concluded that endoplasmic reticulum may play an active role in
defining the position of mitochondrial division sites.
Wang et al. (2012) found that RIP1 (RIPK1; 603453), RIP3 (RIPK3;
605817), and MLKL (615153) formed a necrosis complex in human cell
lines. Upon induction of necrosis by TNF-alpha (191160), both isoforms
of PGAM5 (614939), PGAM5L and PGAM5S, interacted with the RIP1-RIP3-MLKL
necrosis complex and were phosphorylated. Phosphorylated PGAM5S then
recruited DRP1 and activated DRP1 by dephosphorylation, resulting in
mitochondrial fragmentation and execution of necrosis. Blockade of
phosphorylation or dephosphorylation signaling at several points in this
signaling cascade, or knockdown of PGAM5 expression, blocked
TNF-alpha-induced necrosis. Knockdown experiments showed that both PGAM5
isoforms and DRP1, but not RIP1, RIP3, or MLKL, were also involved in
necrosis induced by reactive oxygen species or ionophore-mediated
calcium shock.
Korobova et al. (2013) found that actin polymerization through
endoplasmic reticulum (ER)-localized inverted formin-2 (INF2; 610982)
was required for efficient mitochondrial fission in mammalian cells.
INF2 functioned upstream of DRP1. Actin filaments appeared to accumulate
between mitochondria and INF2-enriched ER membranes at constriction
sites. Thus, INF2-induced actin filaments may drive initial
mitochondrial constriction, which allows DRP1-driven secondary
constriction.
GENE STRUCTURE
Howng et al. (2004) determined that the DNM1L gene contains 20 exons and
spans 64 kb. Exons 15 and 16 are subject to differential splicing. The
5-prime flanking sequence contains 3 GC boxes that concatenate AP2
(TFAP2A; 107580)- and SP1 (189906)-binding motifs, but it lacks TATA or
CAAT consensus sequences. Deletion analysis located the minimal promoter
at nucleotides -108 to -100.
MAPPING
By genomic sequence analysis, Howng et al. (2004) mapped the DNM1L gene
to chromosome 12.
MOLECULAR GENETICS
In a newborn girl with a lethal encephalopathy due to defective
mitochondrial and peroxisomal fission (EMPF; 614388), Waterham et al.
(2007) identified a de novo heterozygous dominant-negative mutation in
the dynamin gene DLP1 (A395D; 603850.0001). The affected infant showed
microcephaly, abnormal brain development, optic atrophy and hypoplasia,
persistent lactic acidemia, and a mildly elevated plasma concentration
of very long-chain fatty acids. Magnetic resonance imaging (MRI)
detected an abnormal gyral pattern in both frontal lobes and was
associated with dysmyelination. Death occurred at 37 days of age.
Immunofluorescence microscopic analyses showed fewer peroxisomes in
fibroblasts from the patient of Waterham et al. (2007) than in
fibroblasts from control subjects. Furthermore, the peroxisomes from the
patient varied markedly in size and were frequently arranged in rows.
This arrangement was similar to that seen in mammalian cells
overexpressing dominant-negative mutant DLP1 or those with DLP1
expression that had been downregulated owing to RNA interference (Koch
et al., 2003; Li and Gould, 2003). Because such mammalian cells also
showed a defect in mitochondrial fission (Smirnova et al., 2001; Yoon et
al., 2001), Waterham et al. (2007) studied the mitochondria of
fibroblasts from the patient using a fluorescent mitochondrial probe.
Mitochondria in the patient's fibroblasts were elongated, tangled,
tubular structures concentrated predominantly around the nucleus.
ANIMAL MODEL
Ishihara et al. (2009) found that Drp1 deletion in mice was embryonic
lethal. Drp1 -/- embryos showed reduced development of the heart and
liver, as well as thinned neural tube cell layer. Electron microscopy
revealed that Drp1 -/- embryos had enlarged mitochondria with normal
cristae and cytochrome c oxidase (see 516030) activity. Embryonic
fibroblasts and stem cells from Drp1 -/- mice were healthy and
proliferated normally. The ER and Golgi of Drp1 -/- cells appeared
normal, but their mitochondria were abnormally extended and clustered
near the nucleus. Peroxisomes were also swollen in Drp1 -/- cells.
Cytokinesis in Drp1 -/- fibroblasts proceeded asymmetrically, with
filamentous and highly clustered mitochondria cleaved at a constriction
site of the cell in concert with cytokinesis and segregated unequally
into the daughter cells. Treatment of Drp1 -/- cells with proapoptotic
reagents suggested that Drp1 is involved in later apoptotic events,
including cytochrome c release and caspase activation. Mice with neural
cell-specific Drp1 deletion (NS-Drp1 -/- mice) died shortly after birth
as a result of brain hypoplasia and apoptosis. Primary cultures of
NS-Drp1 -/- mouse forebrain showed decreased number of neurites and
defective synapse formation, suggesting that aggregated mitochondria
fail to distribute properly within neural cell processes. NS-Drp1 -/-
neuronal cells were also highly sensitive to Ca(2+)-dependent apoptosis.
*FIELD* AV
.0001
ENCEPHALOPATHY, LETHAL, DUE TO DEFECTIVE MITOCHONDRIAL AND PEROXISOMAL
FISSION
DNM1L, ALA395ASP
In an infant with a lethal encephalopathy due to defective mitochondrial
and peroxisomal fission (EMPF; 614388), Waterham et al. (2007) found
heterozygosity for a 1184C-A transversion in the DNM1L gene that
resulted in an ala395-to-asp (A395D) substitution in the middle domain
of the protein. The mutation was not found in genomic DNA from blood
cells from either parent, indicating that the mutation either was de
novo or was present only in germline cells of 1 parent. The patient
presented in the first days of life with microcephaly, abnormal brain
development, optic atrophy and hypoplasia, and lactic acidemia, and died
at age 37 days. Overexpression of mutant DNM1L from the patient in
fibroblasts from control subjects induced aberrant mitochondrial and
peroxisomal phenotypes, indicating that the mutation acted in a
dominant-negative manner.
*FIELD* RF
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*FIELD* CN
Ada Hamosh - updated: 2/21/2013
Patricia A. Hartz - updated: 10/26/2012
Ada Hamosh - updated: 1/4/2012
Patricia A. Hartz - updated: 8/25/2011
Patricia A. Hartz - updated: 8/22/2011
George E. Tiller - updated: 7/7/2010
Patricia A. Hartz - updated: 1/19/2010
Ada Hamosh - updated: 6/16/2009
Victor A. McKusick - updated: 11/19/2007
Ada Hamosh - updated: 4/15/2005
Patricia A. Hartz - updated: 2/11/2004
*FIELD* CD
Patti M. Sherman: 5/26/1999
*FIELD* ED
mgross: 03/29/2013
alopez: 2/26/2013
terry: 2/21/2013
carol: 2/6/2013
mgross: 11/16/2012
terry: 10/26/2012
alopez: 1/6/2012
terry: 1/4/2012
carol: 12/12/2011
ckniffin: 12/12/2011
mgross: 8/26/2011
terry: 8/25/2011
mgross: 8/24/2011
terry: 8/22/2011
alopez: 7/20/2010
terry: 7/7/2010
mgross: 1/25/2010
terry: 1/19/2010
alopez: 6/22/2009
terry: 6/16/2009
carol: 10/15/2008
alopez: 11/19/2007
alopez: 4/22/2005
terry: 4/15/2005
mgross: 3/5/2004
cwells: 3/3/2004
terry: 2/11/2004
carol: 5/25/2000
psherman: 4/17/2000
psherman: 5/27/1999
mgross: 5/27/1999
psherman: 5/27/1999
MIM
614388
*RECORD*
*FIELD* NO
614388
*FIELD* TI
#614388 ENCEPHALOPATHY, LETHAL, DUE TO DEFECTIVE MITOCHONDRIAL AND PEROXISOMAL
FISSION; EMPF
read more*FIELD* TX
A number sign (#) is used with this entry because lethal encephalopathy
due to defective mitochondrial and peroxisomal fission (EMPF) is caused
by heterozygous mutation in the DNM1L gene (603850), encoding the
dynamin-1-like protein, on chromosome 12p.
DESCRIPTION
Encephalopathy due to defective mitochondrial and peroxisomal fission is
a rare autosomal dominant systemic disorder resulting in lack of
neurologic development and death in infancy (summary by Waterham et al.,
2007).
CLINICAL FEATURES
Waterham et al. (2007) reported a newborn girl, born of unrelated
Caucasian parents of British ancestry, with a systemic disorder
resulting in death in infancy. The mother noted diminished fetal
movements during pregnancy. After birth, the infant was well for several
days, but presented in the first week of life with poor feeding and
neurologic impairment, including hypotonia, little spontaneous movement,
no tendon reflexes, no response to light stimulation, and poor visual
fixation. She was mildly dysmorphic, with microcephaly, deep-set eyes,
and a pointed chin. Optic discs were pale and cupped, and MRI showed an
abnormal gyral pattern in both frontal lobes that extended to the
perisylvian areas and was associated with dysmyelination. Laboratory
studies showed persistent lactic acidemia and mildly elevated plasma
concentration of very long-chain fatty acids. She died suddenly at 37
days of age. Studies of patient fibroblasts did not show defects in
mitochondrial oxidative phosphorylation or in mitochondrial complex
activities, and muscle biopsy was essentially normal with no ragged red
fibers. However, immunofluorescence microscopic analyses showed fewer
peroxisomes in fibroblasts compared to controls, and the peroxisomes
varied markedly in size and were frequently arranged in rows. This
arrangement was similar to that seen in mammalian cells overexpressing
dominant-negative mutant DLP1 or those with DLP1 expression that had
been downregulated owing to RNA interference (Koch et al., 2003; Li and
Gould, 2003). Because such mammalian cells also showed a defect in
mitochondrial fission (Smirnova et al., 2001; Yoon et al., 2001),
Waterham et al. (2007) studied the mitochondria of fibroblasts from the
patient using a fluorescent mitochondrial probe. Mitochondria in the
patient's fibroblasts were elongated, tangled, tubular structures
concentrated predominantly around the nucleus.
MOLECULAR GENETICS
In a newborn girl with a systemic lethal disorder and abnormal
peroxisomes and mitochondria in fibroblast studies, Waterham et al.
(2007) identified a de novo heterozygous mutation in the DNM1L gene
(A395D; 603850.0001). The mutation was associated with a severe defect
in the fission of both mitochondria and peroxisomes, indicating a
dominant-negative effect.
*FIELD* RF
1. Koch, A.; Thiemann, M.; Grabenbauer, M.; Yoon, Y.; McNiven, M.
A.; Schrader, M.: Dynamin-like protein 1 is involved in peroxisomal
fission. J. Biol. Chem. 278: 8597-8605, 2003.
2. Li, X.; Gould, S. J.: The dynamin-like GTPase DLP1 is essential
for peroxisome division and is recruited to peroxisomes in part by
PEX11. J. Biol. Chem. 278: 17012-17020, 2003.
3. Smirnova, E.; Griparic, L.; Shurland, D.-L.; van der Bliek, A.
M.: Dynamin-related protein Drp1 is required for mitochondrial division
in mammalian cells. Molec. Biol. Cell 12: 2245-2256, 2001.
4. Waterham, H. R.; Koster, J.; van Roermund, C. W. T.; Mooyer, P.
A. W.; Wanders, R. J. A.; Leonard, J. V.: A lethal defect of mitochondrial
and peroxisomal fission. New Eng. J. Med. 356: 1736-1741, 2007.
5. Yoon, Y.; Pitts, K. R.; McNiven, M. A.: Mammalian dynamin-like
protein DLP1 tubulates membranes. Molec. Biol. Cell 12: 2894-2905,
2001.
*FIELD* CS
INHERITANCE:
Autosomal dominant
GROWTH:
[Other];
Poor feeding;
Failure to thrive
HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Pointed chin;
[Eyes];
Deep-set eyes;
Optic atrophy;
Cupped optic discs;
Poor visual fixation;
Nystagmus, horizontal
NEUROLOGIC:
[Central nervous system];
Hypotonia;
No developmental progress;
Little spontaneous movement;
Brain MRI shows abnormal gyral pattern in frontal lobes;
Dysmyelination;
[Peripheral nervous system];
Areflexia
METABOLIC FEATURES:
Lactic acidosis
PRENATAL MANIFESTATIONS:
[Movement];
Decreased fetal movement
LABORATORY ABNORMALITIES:
Increased serum and CSF lactate;
Fibroblasts show decreased peroxisomes arranged in rows;
Fibroblasts show elongated, tangled, tubular mitochondria;
Defect in mitochondrial and peroxisomal fission
MISCELLANEOUS:
Onset in first days of life;
Death in infancy;
One patient has been reported (as of December 2011)
MOLECULAR BASIS:
Caused by mutation in the dynamin 1-like gene (DNM1L, 603850.0001)
*FIELD* CD
Cassandra L. Kniffin: 12/12/2011
*FIELD* ED
joanna: 12/20/2011
ckniffin: 12/12/2011
*FIELD* CD
Cassandra L. Kniffin: 12/12/2011
*FIELD* ED
carol: 12/12/2011
ckniffin: 12/12/2011
*RECORD*
*FIELD* NO
614388
*FIELD* TI
#614388 ENCEPHALOPATHY, LETHAL, DUE TO DEFECTIVE MITOCHONDRIAL AND PEROXISOMAL
FISSION; EMPF
read more*FIELD* TX
A number sign (#) is used with this entry because lethal encephalopathy
due to defective mitochondrial and peroxisomal fission (EMPF) is caused
by heterozygous mutation in the DNM1L gene (603850), encoding the
dynamin-1-like protein, on chromosome 12p.
DESCRIPTION
Encephalopathy due to defective mitochondrial and peroxisomal fission is
a rare autosomal dominant systemic disorder resulting in lack of
neurologic development and death in infancy (summary by Waterham et al.,
2007).
CLINICAL FEATURES
Waterham et al. (2007) reported a newborn girl, born of unrelated
Caucasian parents of British ancestry, with a systemic disorder
resulting in death in infancy. The mother noted diminished fetal
movements during pregnancy. After birth, the infant was well for several
days, but presented in the first week of life with poor feeding and
neurologic impairment, including hypotonia, little spontaneous movement,
no tendon reflexes, no response to light stimulation, and poor visual
fixation. She was mildly dysmorphic, with microcephaly, deep-set eyes,
and a pointed chin. Optic discs were pale and cupped, and MRI showed an
abnormal gyral pattern in both frontal lobes that extended to the
perisylvian areas and was associated with dysmyelination. Laboratory
studies showed persistent lactic acidemia and mildly elevated plasma
concentration of very long-chain fatty acids. She died suddenly at 37
days of age. Studies of patient fibroblasts did not show defects in
mitochondrial oxidative phosphorylation or in mitochondrial complex
activities, and muscle biopsy was essentially normal with no ragged red
fibers. However, immunofluorescence microscopic analyses showed fewer
peroxisomes in fibroblasts compared to controls, and the peroxisomes
varied markedly in size and were frequently arranged in rows. This
arrangement was similar to that seen in mammalian cells overexpressing
dominant-negative mutant DLP1 or those with DLP1 expression that had
been downregulated owing to RNA interference (Koch et al., 2003; Li and
Gould, 2003). Because such mammalian cells also showed a defect in
mitochondrial fission (Smirnova et al., 2001; Yoon et al., 2001),
Waterham et al. (2007) studied the mitochondria of fibroblasts from the
patient using a fluorescent mitochondrial probe. Mitochondria in the
patient's fibroblasts were elongated, tangled, tubular structures
concentrated predominantly around the nucleus.
MOLECULAR GENETICS
In a newborn girl with a systemic lethal disorder and abnormal
peroxisomes and mitochondria in fibroblast studies, Waterham et al.
(2007) identified a de novo heterozygous mutation in the DNM1L gene
(A395D; 603850.0001). The mutation was associated with a severe defect
in the fission of both mitochondria and peroxisomes, indicating a
dominant-negative effect.
*FIELD* RF
1. Koch, A.; Thiemann, M.; Grabenbauer, M.; Yoon, Y.; McNiven, M.
A.; Schrader, M.: Dynamin-like protein 1 is involved in peroxisomal
fission. J. Biol. Chem. 278: 8597-8605, 2003.
2. Li, X.; Gould, S. J.: The dynamin-like GTPase DLP1 is essential
for peroxisome division and is recruited to peroxisomes in part by
PEX11. J. Biol. Chem. 278: 17012-17020, 2003.
3. Smirnova, E.; Griparic, L.; Shurland, D.-L.; van der Bliek, A.
M.: Dynamin-related protein Drp1 is required for mitochondrial division
in mammalian cells. Molec. Biol. Cell 12: 2245-2256, 2001.
4. Waterham, H. R.; Koster, J.; van Roermund, C. W. T.; Mooyer, P.
A. W.; Wanders, R. J. A.; Leonard, J. V.: A lethal defect of mitochondrial
and peroxisomal fission. New Eng. J. Med. 356: 1736-1741, 2007.
5. Yoon, Y.; Pitts, K. R.; McNiven, M. A.: Mammalian dynamin-like
protein DLP1 tubulates membranes. Molec. Biol. Cell 12: 2894-2905,
2001.
*FIELD* CS
INHERITANCE:
Autosomal dominant
GROWTH:
[Other];
Poor feeding;
Failure to thrive
HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Pointed chin;
[Eyes];
Deep-set eyes;
Optic atrophy;
Cupped optic discs;
Poor visual fixation;
Nystagmus, horizontal
NEUROLOGIC:
[Central nervous system];
Hypotonia;
No developmental progress;
Little spontaneous movement;
Brain MRI shows abnormal gyral pattern in frontal lobes;
Dysmyelination;
[Peripheral nervous system];
Areflexia
METABOLIC FEATURES:
Lactic acidosis
PRENATAL MANIFESTATIONS:
[Movement];
Decreased fetal movement
LABORATORY ABNORMALITIES:
Increased serum and CSF lactate;
Fibroblasts show decreased peroxisomes arranged in rows;
Fibroblasts show elongated, tangled, tubular mitochondria;
Defect in mitochondrial and peroxisomal fission
MISCELLANEOUS:
Onset in first days of life;
Death in infancy;
One patient has been reported (as of December 2011)
MOLECULAR BASIS:
Caused by mutation in the dynamin 1-like gene (DNM1L, 603850.0001)
*FIELD* CD
Cassandra L. Kniffin: 12/12/2011
*FIELD* ED
joanna: 12/20/2011
ckniffin: 12/12/2011
*FIELD* CD
Cassandra L. Kniffin: 12/12/2011
*FIELD* ED
carol: 12/12/2011
ckniffin: 12/12/2011