Full text data of DCTN4
DCTN4
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Dynactin subunit 4; Dyn4 (Dynactin subunit p62)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Dynactin subunit 4; Dyn4 (Dynactin subunit p62)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q9UJW0
ID DCTN4_HUMAN Reviewed; 460 AA.
AC Q9UJW0; B3KWW0; D3DQH0; E5RGT5; Q8TAN8;
DT 26-APR-2005, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-MAY-2000, sequence version 1.
DT 22-JAN-2014, entry version 95.
DE RecName: Full=Dynactin subunit 4;
DE Short=Dyn4;
DE AltName: Full=Dynactin subunit p62;
GN Name=DCTN4;
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), SUBUNIT, AND SUBCELLULAR
RP LOCATION.
RC TISSUE=Neuron;
RX PubMed=10671518; DOI=10.1074/jbc.275.7.4834;
RA Karki S., Tokito M.K., Holzbaur E.L.F.;
RT "A dynactin subunit with a highly conserved cysteine-rich motif
RT interacts directly with Arp1.";
RL J. Biol. Chem. 275:4834-4839(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT
RP LEU-342.
RC TISSUE=Testis;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T.,
RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
RA Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
RP THR-95.
RC TISSUE=Brain;
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 [6]
RP INTERACTION WITH ATP7B, AND MUTAGENESIS OF CYS-30; CYS-33; CYS-51;
RP CYS-54; CYS-70; CYS-73; CYS-76; CYS-79; CYS-111; CYS-114; CYS-277 AND
RP CYS-280.
RX PubMed=16554302; DOI=10.1074/jbc.M512745200;
RA Lim C.M., Cater M.A., Mercer J.F., La Fontaine S.;
RT "Copper-dependent interaction of dynactin subunit p62 with the N
RT terminus of ATP7B but not ATP7A.";
RL J. Biol. Chem. 281:14006-14014(2006).
RN [7]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
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 [8]
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 [9]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
CC -!- FUNCTION: Could have a dual role in dynein targeting and in
CC ACTR1A/Arp1 subunit of dynactin pointed-end capping. Could be
CC involved in ACTR1A pointed-end binding and in additional roles in
CC linking dynein and dynactin to the cortical cytoskeleton.
CC -!- SUBUNIT: Member of the pointed-end complex of the dynactin
CC shoulder complex which contains DCTN4, DCTN5 and DCTN6 subunits
CC and ACTR10 (By similarity). Binds directly to the ACTR1A subunit
CC of dynactin. Interacts with ATP7B, but not ATP7A, in a copper-
CC dependent manner. Interacts with ANK2; this interaction is
CC required for localization at costameres (By similarity).
CC -!- INTERACTION:
CC Q01484:ANK2; NbExp=1; IntAct=EBI-2134033, EBI-941975;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton. Cytoplasm,
CC cytoskeleton, microtubule organizing center, centrosome. Note=In
CC skeletal muscles, demonstrates a punctate distribution along
CC costameres (By similarity). Has a punctate cytoplasmic
CC distribution as well as centrosomal distribution typical of
CC dynactin. Overexpression does not disrupt microtubule organization
CC or the integrity of the Golgi but does cause both cytosolic and
CC nuclear distribution, suggesting that this polypeptide may be
CC targeted to the nucleus at very high expression levels.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q9UJW0-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9UJW0-2; Sequence=VSP_041306;
CC Name=3;
CC IsoId=Q9UJW0-3; Sequence=VSP_041307;
CC -!- SIMILARITY: Belongs to the dynactin subunit 4 family.
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DR EMBL; AF195120; AAF03896.1; -; mRNA.
DR EMBL; AK125973; BAG54272.1; -; mRNA.
DR EMBL; AK000299; BAA91066.1; -; mRNA.
DR EMBL; AC008450; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC008453; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471062; EAW61706.1; -; Genomic_DNA.
DR EMBL; CH471062; EAW61707.1; -; Genomic_DNA.
DR EMBL; CH471062; EAW61709.1; -; Genomic_DNA.
DR EMBL; BC026323; AAH26323.1; -; mRNA.
DR RefSeq; NP_001129115.1; NM_001135643.1.
DR RefSeq; NP_001129116.1; NM_001135644.1.
DR RefSeq; NP_057305.1; NM_016221.3.
DR UniGene; Hs.675564; -.
DR ProteinModelPortal; Q9UJW0; -.
DR IntAct; Q9UJW0; 9.
DR MINT; MINT-4535396; -.
DR STRING; 9606.ENSP00000414906; -.
DR PhosphoSite; Q9UJW0; -.
DR DMDM; 62900106; -.
DR PaxDb; Q9UJW0; -.
DR PeptideAtlas; Q9UJW0; -.
DR PRIDE; Q9UJW0; -.
DR DNASU; 51164; -.
DR Ensembl; ENST00000424236; ENSP00000411251; ENSG00000132912.
DR Ensembl; ENST00000446090; ENSP00000414906; ENSG00000132912.
DR Ensembl; ENST00000447998; ENSP00000416968; ENSG00000132912.
DR GeneID; 51164; -.
DR KEGG; hsa:51164; -.
DR UCSC; uc003lsu.3; human.
DR CTD; 51164; -.
DR GeneCards; GC05M150068; -.
DR HGNC; HGNC:15518; DCTN4.
DR HPA; CAB017532; -.
DR MIM; 614758; gene.
DR neXtProt; NX_Q9UJW0; -.
DR Orphanet; 586; Cystic fibrosis.
DR PharmGKB; PA27183; -.
DR eggNOG; NOG147462; -.
DR HOGENOM; HOG000007947; -.
DR HOVERGEN; HBG051324; -.
DR InParanoid; Q9UJW0; -.
DR KO; K10426; -.
DR OMA; SYIPEVR; -.
DR OrthoDB; EOG7SXW2X; -.
DR PhylomeDB; Q9UJW0; -.
DR Reactome; REACT_6900; Immune System.
DR GenomeRNAi; 51164; -.
DR NextBio; 54093; -.
DR PRO; PR:Q9UJW0; -.
DR ArrayExpress; Q9UJW0; -.
DR Bgee; Q9UJW0; -.
DR CleanEx; HS_DCTN4; -.
DR Genevestigator; Q9UJW0; -.
DR GO; GO:0005813; C:centrosome; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005869; C:dynactin complex; IEA:InterPro.
DR GO; GO:0005634; C:nucleus; TAS:ProtInc.
DR GO; GO:0019886; P:antigen processing and presentation of exogenous peptide antigen via MHC class II; TAS:Reactome.
DR InterPro; IPR008603; Dynactin_p62.
DR PANTHER; PTHR13034; PTHR13034; 1.
DR Pfam; PF05502; Dynactin_p62; 2.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Coiled coil; Complete proteome;
KW Cytoplasm; Cytoskeleton; Phosphoprotein; Polymorphism;
KW Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 460 Dynactin subunit 4.
FT /FTId=PRO_0000079823.
FT COILED 152 172 Potential.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 407 407 Phosphothreonine (By similarity).
FT VAR_SEQ 1 57 Missing (in isoform 2).
FT /FTId=VSP_041306.
FT VAR_SEQ 179 179 S -> SQHTIHVV (in isoform 3).
FT /FTId=VSP_041307.
FT VARIANT 95 95 P -> T (in dbSNP:rs11550931).
FT /FTId=VAR_054037.
FT VARIANT 263 263 Y -> C (in dbSNP:rs35772018).
FT /FTId=VAR_033847.
FT VARIANT 342 342 F -> L (in dbSNP:rs11954652).
FT /FTId=VAR_024336.
FT VARIANT 438 438 S -> N (in dbSNP:rs3733923).
FT /FTId=VAR_024337.
FT MUTAGEN 30 30 C->S: Loss of ATP7B-binding; when
FT associated with S-33; S-51; S-54; S-70,
FT S-73; S-76; S-79; S-111; S-114; S-277 and
FT S-280.
FT MUTAGEN 33 33 C->S: Loss of ATP7B-binding; when
FT associated with S-30; S-51; S-54; S-70,
FT S-73; S-76; S-79; S-111; S-114; S-277 and
FT S-280.
FT MUTAGEN 51 51 C->S: Loss of ATP7B-binding; when
FT associated with S-30; S-33; S-54; S-70,
FT S-73; S-76; S-79; S-111; S-114; S-277 and
FT S-280.
FT MUTAGEN 54 54 C->S: Loss of ATP7B-binding; when
FT associated with S-30; S-33; S-51; S-70,
FT S-73; S-76; S-79; S-111; S-114; S-277 and
FT S-280.
FT MUTAGEN 70 70 C->S: Loss of ATP7B-binding; when
FT associated with S-30; S-33; S-51; S-54,
FT S-73; S-76; S-79; S-111; S-114; S-277 and
FT S-280.
FT MUTAGEN 73 73 C->S: Loss of ATP7B-binding; when
FT associated with S-30; S-33; S-51; S-54,
FT S-70; S-76; S-79; S-111; S-114; S-277 and
FT S-280.
FT MUTAGEN 76 76 C->S: Loss of ATP7B-binding; when
FT associated with S-30; S-33; S-51; S-54,
FT S-70; S-73; S-79; S-111; S-114; S-277 and
FT S-280.
FT MUTAGEN 79 79 C->S: Loss of ATP7B-binding; when
FT associated with S-30; S-33; S-51; S-54,
FT S-70; S-73; S-76; S-111; S-114; S-277 and
FT S-280.
FT MUTAGEN 111 111 C->S: Loss of ATP7B-binding; when
FT associated with S-30; S-33; S-51; S-54,
FT S-70; S-73; S-76; S-79; S-114; S-277 and
FT S-280.
FT MUTAGEN 114 114 C->S: Loss of ATP7B-binding; when
FT associated with S-30; S-33; S-51; S-54,
FT S-70; S-73; S-76; S-79; S-111; S-277 and
FT S-280.
FT MUTAGEN 277 277 C->S: Loss of ATP7B-binding; when
FT associated with S-30; S-33; S-51; S-54,
FT S-70; S-73; S-76; S-79; S-111; S-114 and
FT S-280.
FT MUTAGEN 280 280 C->S: Loss of ATP7B-binding; when
FT associated with S-30; S-33; S-51; S-54,
FT S-70; S-73; S-76; S-79; S-111; S-114 and
FT S-277.
SQ SEQUENCE 460 AA; 52337 MW; 2105D6C0A713B11D CRC64;
MASLLQSDRV LYLVQGEKKV RAPLSQLYFC RYCSELRSLE CVSHEVDSHY CPSCLENMPS
AEAKLKKNRC ANCFDCPGCM HTLSTRATSI STQLPDDPAK TTMKKAYYLA CGFCRWTSRD
VGMADKSVAS GGWQEPENPH TQRMNKLIEY YQQLAQKEKV ERDRKKLARR RNYMPLAFSD
KYGLGTRLQR PRAGASISTL AGLSLKEGED QKEIKIEPAQ AVDEVEPLPE DYYTRPVNLT
EVTTLQQRLL QPDFQPVCAS QLYPRHKHLL IKRSLRCRKC EHNLSKPEFN PTSIKFKIQL
VAVNYIPEVR IMSIPNLRYM KESQVLLTLT NPVENLTHVT LFECEEGDPD DINSTAKVVV
PPKELVLAGK DAAAEYDELA EPQDFQDDPD IIAFRKANKV GIFIKVTPQR EEGEVTVCFK
MKHDFKNLAA PIRPIEESDQ GTEVIWLTQH VELSLGPLLP
//
ID DCTN4_HUMAN Reviewed; 460 AA.
AC Q9UJW0; B3KWW0; D3DQH0; E5RGT5; Q8TAN8;
DT 26-APR-2005, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-MAY-2000, sequence version 1.
DT 22-JAN-2014, entry version 95.
DE RecName: Full=Dynactin subunit 4;
DE Short=Dyn4;
DE AltName: Full=Dynactin subunit p62;
GN Name=DCTN4;
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), SUBUNIT, AND SUBCELLULAR
RP LOCATION.
RC TISSUE=Neuron;
RX PubMed=10671518; DOI=10.1074/jbc.275.7.4834;
RA Karki S., Tokito M.K., Holzbaur E.L.F.;
RT "A dynactin subunit with a highly conserved cysteine-rich motif
RT interacts directly with Arp1.";
RL J. Biol. Chem. 275:4834-4839(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT
RP LEU-342.
RC TISSUE=Testis;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T.,
RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
RA Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
RP THR-95.
RC TISSUE=Brain;
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 [6]
RP INTERACTION WITH ATP7B, AND MUTAGENESIS OF CYS-30; CYS-33; CYS-51;
RP CYS-54; CYS-70; CYS-73; CYS-76; CYS-79; CYS-111; CYS-114; CYS-277 AND
RP CYS-280.
RX PubMed=16554302; DOI=10.1074/jbc.M512745200;
RA Lim C.M., Cater M.A., Mercer J.F., La Fontaine S.;
RT "Copper-dependent interaction of dynactin subunit p62 with the N
RT terminus of ATP7B but not ATP7A.";
RL J. Biol. Chem. 281:14006-14014(2006).
RN [7]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
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 [8]
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 [9]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
CC -!- FUNCTION: Could have a dual role in dynein targeting and in
CC ACTR1A/Arp1 subunit of dynactin pointed-end capping. Could be
CC involved in ACTR1A pointed-end binding and in additional roles in
CC linking dynein and dynactin to the cortical cytoskeleton.
CC -!- SUBUNIT: Member of the pointed-end complex of the dynactin
CC shoulder complex which contains DCTN4, DCTN5 and DCTN6 subunits
CC and ACTR10 (By similarity). Binds directly to the ACTR1A subunit
CC of dynactin. Interacts with ATP7B, but not ATP7A, in a copper-
CC dependent manner. Interacts with ANK2; this interaction is
CC required for localization at costameres (By similarity).
CC -!- INTERACTION:
CC Q01484:ANK2; NbExp=1; IntAct=EBI-2134033, EBI-941975;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton. Cytoplasm,
CC cytoskeleton, microtubule organizing center, centrosome. Note=In
CC skeletal muscles, demonstrates a punctate distribution along
CC costameres (By similarity). Has a punctate cytoplasmic
CC distribution as well as centrosomal distribution typical of
CC dynactin. Overexpression does not disrupt microtubule organization
CC or the integrity of the Golgi but does cause both cytosolic and
CC nuclear distribution, suggesting that this polypeptide may be
CC targeted to the nucleus at very high expression levels.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q9UJW0-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9UJW0-2; Sequence=VSP_041306;
CC Name=3;
CC IsoId=Q9UJW0-3; Sequence=VSP_041307;
CC -!- SIMILARITY: Belongs to the dynactin subunit 4 family.
CC -----------------------------------------------------------------------
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CC Distributed under the Creative Commons Attribution-NoDerivs License
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DR EMBL; AF195120; AAF03896.1; -; mRNA.
DR EMBL; AK125973; BAG54272.1; -; mRNA.
DR EMBL; AK000299; BAA91066.1; -; mRNA.
DR EMBL; AC008450; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC008453; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471062; EAW61706.1; -; Genomic_DNA.
DR EMBL; CH471062; EAW61707.1; -; Genomic_DNA.
DR EMBL; CH471062; EAW61709.1; -; Genomic_DNA.
DR EMBL; BC026323; AAH26323.1; -; mRNA.
DR RefSeq; NP_001129115.1; NM_001135643.1.
DR RefSeq; NP_001129116.1; NM_001135644.1.
DR RefSeq; NP_057305.1; NM_016221.3.
DR UniGene; Hs.675564; -.
DR ProteinModelPortal; Q9UJW0; -.
DR IntAct; Q9UJW0; 9.
DR MINT; MINT-4535396; -.
DR STRING; 9606.ENSP00000414906; -.
DR PhosphoSite; Q9UJW0; -.
DR DMDM; 62900106; -.
DR PaxDb; Q9UJW0; -.
DR PeptideAtlas; Q9UJW0; -.
DR PRIDE; Q9UJW0; -.
DR DNASU; 51164; -.
DR Ensembl; ENST00000424236; ENSP00000411251; ENSG00000132912.
DR Ensembl; ENST00000446090; ENSP00000414906; ENSG00000132912.
DR Ensembl; ENST00000447998; ENSP00000416968; ENSG00000132912.
DR GeneID; 51164; -.
DR KEGG; hsa:51164; -.
DR UCSC; uc003lsu.3; human.
DR CTD; 51164; -.
DR GeneCards; GC05M150068; -.
DR HGNC; HGNC:15518; DCTN4.
DR HPA; CAB017532; -.
DR MIM; 614758; gene.
DR neXtProt; NX_Q9UJW0; -.
DR Orphanet; 586; Cystic fibrosis.
DR PharmGKB; PA27183; -.
DR eggNOG; NOG147462; -.
DR HOGENOM; HOG000007947; -.
DR HOVERGEN; HBG051324; -.
DR InParanoid; Q9UJW0; -.
DR KO; K10426; -.
DR OMA; SYIPEVR; -.
DR OrthoDB; EOG7SXW2X; -.
DR PhylomeDB; Q9UJW0; -.
DR Reactome; REACT_6900; Immune System.
DR GenomeRNAi; 51164; -.
DR NextBio; 54093; -.
DR PRO; PR:Q9UJW0; -.
DR ArrayExpress; Q9UJW0; -.
DR Bgee; Q9UJW0; -.
DR CleanEx; HS_DCTN4; -.
DR Genevestigator; Q9UJW0; -.
DR GO; GO:0005813; C:centrosome; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005869; C:dynactin complex; IEA:InterPro.
DR GO; GO:0005634; C:nucleus; TAS:ProtInc.
DR GO; GO:0019886; P:antigen processing and presentation of exogenous peptide antigen via MHC class II; TAS:Reactome.
DR InterPro; IPR008603; Dynactin_p62.
DR PANTHER; PTHR13034; PTHR13034; 1.
DR Pfam; PF05502; Dynactin_p62; 2.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Coiled coil; Complete proteome;
KW Cytoplasm; Cytoskeleton; Phosphoprotein; Polymorphism;
KW Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 460 Dynactin subunit 4.
FT /FTId=PRO_0000079823.
FT COILED 152 172 Potential.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 407 407 Phosphothreonine (By similarity).
FT VAR_SEQ 1 57 Missing (in isoform 2).
FT /FTId=VSP_041306.
FT VAR_SEQ 179 179 S -> SQHTIHVV (in isoform 3).
FT /FTId=VSP_041307.
FT VARIANT 95 95 P -> T (in dbSNP:rs11550931).
FT /FTId=VAR_054037.
FT VARIANT 263 263 Y -> C (in dbSNP:rs35772018).
FT /FTId=VAR_033847.
FT VARIANT 342 342 F -> L (in dbSNP:rs11954652).
FT /FTId=VAR_024336.
FT VARIANT 438 438 S -> N (in dbSNP:rs3733923).
FT /FTId=VAR_024337.
FT MUTAGEN 30 30 C->S: Loss of ATP7B-binding; when
FT associated with S-33; S-51; S-54; S-70,
FT S-73; S-76; S-79; S-111; S-114; S-277 and
FT S-280.
FT MUTAGEN 33 33 C->S: Loss of ATP7B-binding; when
FT associated with S-30; S-51; S-54; S-70,
FT S-73; S-76; S-79; S-111; S-114; S-277 and
FT S-280.
FT MUTAGEN 51 51 C->S: Loss of ATP7B-binding; when
FT associated with S-30; S-33; S-54; S-70,
FT S-73; S-76; S-79; S-111; S-114; S-277 and
FT S-280.
FT MUTAGEN 54 54 C->S: Loss of ATP7B-binding; when
FT associated with S-30; S-33; S-51; S-70,
FT S-73; S-76; S-79; S-111; S-114; S-277 and
FT S-280.
FT MUTAGEN 70 70 C->S: Loss of ATP7B-binding; when
FT associated with S-30; S-33; S-51; S-54,
FT S-73; S-76; S-79; S-111; S-114; S-277 and
FT S-280.
FT MUTAGEN 73 73 C->S: Loss of ATP7B-binding; when
FT associated with S-30; S-33; S-51; S-54,
FT S-70; S-76; S-79; S-111; S-114; S-277 and
FT S-280.
FT MUTAGEN 76 76 C->S: Loss of ATP7B-binding; when
FT associated with S-30; S-33; S-51; S-54,
FT S-70; S-73; S-79; S-111; S-114; S-277 and
FT S-280.
FT MUTAGEN 79 79 C->S: Loss of ATP7B-binding; when
FT associated with S-30; S-33; S-51; S-54,
FT S-70; S-73; S-76; S-111; S-114; S-277 and
FT S-280.
FT MUTAGEN 111 111 C->S: Loss of ATP7B-binding; when
FT associated with S-30; S-33; S-51; S-54,
FT S-70; S-73; S-76; S-79; S-114; S-277 and
FT S-280.
FT MUTAGEN 114 114 C->S: Loss of ATP7B-binding; when
FT associated with S-30; S-33; S-51; S-54,
FT S-70; S-73; S-76; S-79; S-111; S-277 and
FT S-280.
FT MUTAGEN 277 277 C->S: Loss of ATP7B-binding; when
FT associated with S-30; S-33; S-51; S-54,
FT S-70; S-73; S-76; S-79; S-111; S-114 and
FT S-280.
FT MUTAGEN 280 280 C->S: Loss of ATP7B-binding; when
FT associated with S-30; S-33; S-51; S-54,
FT S-70; S-73; S-76; S-79; S-111; S-114 and
FT S-277.
SQ SEQUENCE 460 AA; 52337 MW; 2105D6C0A713B11D CRC64;
MASLLQSDRV LYLVQGEKKV RAPLSQLYFC RYCSELRSLE CVSHEVDSHY CPSCLENMPS
AEAKLKKNRC ANCFDCPGCM HTLSTRATSI STQLPDDPAK TTMKKAYYLA CGFCRWTSRD
VGMADKSVAS GGWQEPENPH TQRMNKLIEY YQQLAQKEKV ERDRKKLARR RNYMPLAFSD
KYGLGTRLQR PRAGASISTL AGLSLKEGED QKEIKIEPAQ AVDEVEPLPE DYYTRPVNLT
EVTTLQQRLL QPDFQPVCAS QLYPRHKHLL IKRSLRCRKC EHNLSKPEFN PTSIKFKIQL
VAVNYIPEVR IMSIPNLRYM KESQVLLTLT NPVENLTHVT LFECEEGDPD DINSTAKVVV
PPKELVLAGK DAAAEYDELA EPQDFQDDPD IIAFRKANKV GIFIKVTPQR EEGEVTVCFK
MKHDFKNLAA PIRPIEESDQ GTEVIWLTQH VELSLGPLLP
//
MIM
614758
*RECORD*
*FIELD* NO
614758
*FIELD* TI
*614758 DYNACTIN 4; DCTN4
;;DYN4;;
DYNACTIN, 62-KD SUBUNIT;;
p62
*FIELD* TX
DESCRIPTION
read more
DCTN4 is a subunit of the 20S dynactin complex. The dynactin complex is
involved in microtubule-dependent vesicular transport, spindle assembly,
and cell division (summary by Karki et al., 2000).
CLONING
By gene dosage analysis and sequencing candidate genes in a YAC contig
covering the critical region of the 5q deletion syndrome (153550),
followed by database analysis, Boultwood et al. (2000) identified a
DCTN4 clone designated 605d01. Northern blot analysis detected a 7.5-kb
DCTN4 transcript in all 15 human tissues examined.
By mass spectrometric analysis of the 62-kD protein that affinity
purified with human dynactin, followed by EST database analysis and PCR
of an NT2 human teratocarcinoma cDNA library, Karki et al. (2000) cloned
DCTN4, which they called p62. The deduced 460-amino acid protein has a
calculated molecular mass of 52.3 kD. It has an N-terminal domain with
11 cysteines, the last 8 of which fit the consensus sequence for a RING
domain predicted to bind 2 Zn(2+) atoms. Northern blot analysis detected
variable expression of an approximately 4.2-kb transcript in all tissues
examined, with highest expression in heart and skeletal muscle.
Immunocytochemical analysis revealed that p62 had a punctate cytoplasmic
distribution as well as a centrosomal distribution typical of dynactin.
By immunohistochemical analysis, Ayalon et al. (2008) showed that Dyn4
colocalized with other dynactin subunits in adult mouse muscle fibers.
Dyn4 localized in a punctate distribution along costamere lines.
GENE FUNCTION
Karki et al. (2000) stated that p62 is present in the dynactin complex
at a stoichiometry of 1 copy per complex and that it localizes at 1 end
of the central ARP1 (ACTR1A; 605143) polymeric filament. Using
biochemical and immunoprecipitation analyses, they showed that p62
associated with the rat 20S dynactin complex. Recombinant human p62
bound immobilized in vitro-translated human ARP1. Overexpression of p62
in PtK2 porcine kidney cells did not disrupt microtubule organization or
the integrity of the Golgi, but it resulted in some p62 nuclear
localization.
ATP7B (606882) localizes to the trans-Golgi network, where it transports
copper to apoceruloplasmin (CP; 117700). When copper levels are in
excess, ATP7B redistributes to a vesicular compartment near the biliary
canalicular membranes, where excess copper is eliminated into bile.
Using a yeast 2-hybrid screen of a human liver cDNA library, Lim et al.
(2006) found that the N-terminal domain of ATP7B, which contains 6
N-terminal metal-binding sites, interacted with the C-terminal domain of
p62. Coimmunoprecipitation analysis revealed that ATP7B, but not ATP7A
(300011), interacted with endogenous p62 in a human fibroblast line.
Depletion of copper reduced interaction of ATP7B with p62. Mutation
analysis revealed that the metal-binding CxxC motifs of ATP7B were
required for its interaction with p62, predominantly CxxC motifs 4
through 6. Lim et al. (2006) concluded that ATP7B is transported along
liver cell microtubules in a copper-dependent manner via interaction
with p62.
By yeast 2-hybrid analysis of a mouse heart cDNA library, Ayalon et al.
(2008) found that Ankb (ANK2; 106410) interacted with Dyn4. Protein
pull-down assays confirmed the interaction. Depletion of Ankb in adult
mouse skeletal muscle fibers disrupted costamere-associated
microtubules, concomitant with loss of costamere-associated Dyn4
expression.
MAPPING
By database and YAC contig analyses, Boultwood et al. (2000) mapped the
DCTN4 gene to chromosome 5q31-q32.
MOLECULAR GENETICS
Emond et al. (2012) used exome sequencing and an extreme phenotype study
design to discover genetic variants influencing Pseudomonas aeruginosa
infection in cystic fibrosis. Forty-three individuals with early age of
onset of chronic P. aeruginosa infection (all below the tenth percentile
of age at onset), and the 48 oldest individuals who had not reached
chronic P. aeruginosa infection (all past the mean age of onset) were
sequenced. After Bonferroni adjustment, a single gene, DCTN4, was
significantly associated with time to chronic P. aeruginosa infection
(naive P = 2.2 x 10(-6); adjusted P = 0.025). Twelve of the 43
individuals in the early extreme sample carried a missense variant in
DCTN4, 9 a phe349-to-leu substitution (F349L; dbSNP rs11954652) and 3 a
tyr270-to-cys substitution (Y270C; dbSNP rs35772018). None of the 48
individuals in the late P. aeruginosa extreme sample had either missense
variant. Subsequently, 696 individuals with varied CFTR genotypes were
studied. Seventy-eight participants were heterozygous and 9 were
homozygous for the F349L (614758.0001) mutation; 15 were heterozygous
for the Y270C (614758.0002) mutation; 1 individual was heterozygous for
both mutations. The presence of at least 1 DCTN4 missense variant was
significantly associated with both early age of first P.
aeruginosa-positive culture (p = 0.01, hazard ratio = 1.4) and with
early age of onset of chronic P. aeruginosa infection (p = 0.004, hazard
ratio = 1.9). The risk was highest in individuals with less selective
bias toward a P. aeruginosa-negative history, i.e., children enrolled
before 1.5 years of age and 103 enrollees who participated in the study
despite a history of P. aeruginosa-positive cultures. No significant
interaction was found between CFTR genotypes and DCTN4 mutations,
although power to detect such an interaction was low.
*FIELD* RF
1. Ayalon, G.; Davis, J. Q.; Scotland, P. B.; Bennett, V.: An ankyrin-based
mechanism for functional organization of dystrophin and dystroglycan. Cell 135:
1189-1200, 2008.
2. Boultwood, J.; Fidler, C.; Strickson, A. J.; Watkins, F.; Kostrzewa,
M.; Jaju, R. J.; Muller, U.; Wainscoat, J. S.: Transcription mapping
of the 5q- syndrome critical region: cloning of two novel genes and
sequencing, expression, and mapping of a further six novel cDNAs. Genomics 66:
26-34, 2000.
3. Emond, M. J.; Louie, T.; Emerson, J.; Zhao, W.; Mathias, R. A.;
Knowles, M. R.; Wright, F. A.; Rieder, M. J.; Tabor, H. K.; Nickerson,
D. A.; Barnes, K. C.; National Heart, Lung, and Blood Institute (NHLBI)
GO Exome Sequencing Project; Lung GO; Gibson, R. L.; Bamshad, M.
J.: Exome sequencing of extreme phenotypes identifies DCTN4 as a
modifier of chronic Pseudomonas aeruginosa infection in cystic fibrosis. Nature
Genet. 44: 886-889, 2012.
4. Karki, S.; Tokito, M. K.; Holzbaur, E. L. F.: A dynactin subunit
with a highly conserved cysteine-rich motif interacts directly with
Arp1. J. Biol. Chem. 275: 4834-4839, 2000.
5. Lim, C. M.; Cater, M. A.; Mercer, J. F. B.; La Fontaine, S.: Copper-dependent
interaction of dynactin subunit p62 with the N terminus of ATP7B but
not ATP7A. J. Biol. Chem. 281: 14006-14014, 2006.
*FIELD* CN
Ada Hamosh - updated: 2/26/2013
*FIELD* CD
Patricia A. Hartz: 8/10/2012
*FIELD* ED
alopez: 03/04/2013
terry: 2/26/2013
mgross: 8/10/2012
*RECORD*
*FIELD* NO
614758
*FIELD* TI
*614758 DYNACTIN 4; DCTN4
;;DYN4;;
DYNACTIN, 62-KD SUBUNIT;;
p62
*FIELD* TX
DESCRIPTION
read more
DCTN4 is a subunit of the 20S dynactin complex. The dynactin complex is
involved in microtubule-dependent vesicular transport, spindle assembly,
and cell division (summary by Karki et al., 2000).
CLONING
By gene dosage analysis and sequencing candidate genes in a YAC contig
covering the critical region of the 5q deletion syndrome (153550),
followed by database analysis, Boultwood et al. (2000) identified a
DCTN4 clone designated 605d01. Northern blot analysis detected a 7.5-kb
DCTN4 transcript in all 15 human tissues examined.
By mass spectrometric analysis of the 62-kD protein that affinity
purified with human dynactin, followed by EST database analysis and PCR
of an NT2 human teratocarcinoma cDNA library, Karki et al. (2000) cloned
DCTN4, which they called p62. The deduced 460-amino acid protein has a
calculated molecular mass of 52.3 kD. It has an N-terminal domain with
11 cysteines, the last 8 of which fit the consensus sequence for a RING
domain predicted to bind 2 Zn(2+) atoms. Northern blot analysis detected
variable expression of an approximately 4.2-kb transcript in all tissues
examined, with highest expression in heart and skeletal muscle.
Immunocytochemical analysis revealed that p62 had a punctate cytoplasmic
distribution as well as a centrosomal distribution typical of dynactin.
By immunohistochemical analysis, Ayalon et al. (2008) showed that Dyn4
colocalized with other dynactin subunits in adult mouse muscle fibers.
Dyn4 localized in a punctate distribution along costamere lines.
GENE FUNCTION
Karki et al. (2000) stated that p62 is present in the dynactin complex
at a stoichiometry of 1 copy per complex and that it localizes at 1 end
of the central ARP1 (ACTR1A; 605143) polymeric filament. Using
biochemical and immunoprecipitation analyses, they showed that p62
associated with the rat 20S dynactin complex. Recombinant human p62
bound immobilized in vitro-translated human ARP1. Overexpression of p62
in PtK2 porcine kidney cells did not disrupt microtubule organization or
the integrity of the Golgi, but it resulted in some p62 nuclear
localization.
ATP7B (606882) localizes to the trans-Golgi network, where it transports
copper to apoceruloplasmin (CP; 117700). When copper levels are in
excess, ATP7B redistributes to a vesicular compartment near the biliary
canalicular membranes, where excess copper is eliminated into bile.
Using a yeast 2-hybrid screen of a human liver cDNA library, Lim et al.
(2006) found that the N-terminal domain of ATP7B, which contains 6
N-terminal metal-binding sites, interacted with the C-terminal domain of
p62. Coimmunoprecipitation analysis revealed that ATP7B, but not ATP7A
(300011), interacted with endogenous p62 in a human fibroblast line.
Depletion of copper reduced interaction of ATP7B with p62. Mutation
analysis revealed that the metal-binding CxxC motifs of ATP7B were
required for its interaction with p62, predominantly CxxC motifs 4
through 6. Lim et al. (2006) concluded that ATP7B is transported along
liver cell microtubules in a copper-dependent manner via interaction
with p62.
By yeast 2-hybrid analysis of a mouse heart cDNA library, Ayalon et al.
(2008) found that Ankb (ANK2; 106410) interacted with Dyn4. Protein
pull-down assays confirmed the interaction. Depletion of Ankb in adult
mouse skeletal muscle fibers disrupted costamere-associated
microtubules, concomitant with loss of costamere-associated Dyn4
expression.
MAPPING
By database and YAC contig analyses, Boultwood et al. (2000) mapped the
DCTN4 gene to chromosome 5q31-q32.
MOLECULAR GENETICS
Emond et al. (2012) used exome sequencing and an extreme phenotype study
design to discover genetic variants influencing Pseudomonas aeruginosa
infection in cystic fibrosis. Forty-three individuals with early age of
onset of chronic P. aeruginosa infection (all below the tenth percentile
of age at onset), and the 48 oldest individuals who had not reached
chronic P. aeruginosa infection (all past the mean age of onset) were
sequenced. After Bonferroni adjustment, a single gene, DCTN4, was
significantly associated with time to chronic P. aeruginosa infection
(naive P = 2.2 x 10(-6); adjusted P = 0.025). Twelve of the 43
individuals in the early extreme sample carried a missense variant in
DCTN4, 9 a phe349-to-leu substitution (F349L; dbSNP rs11954652) and 3 a
tyr270-to-cys substitution (Y270C; dbSNP rs35772018). None of the 48
individuals in the late P. aeruginosa extreme sample had either missense
variant. Subsequently, 696 individuals with varied CFTR genotypes were
studied. Seventy-eight participants were heterozygous and 9 were
homozygous for the F349L (614758.0001) mutation; 15 were heterozygous
for the Y270C (614758.0002) mutation; 1 individual was heterozygous for
both mutations. The presence of at least 1 DCTN4 missense variant was
significantly associated with both early age of first P.
aeruginosa-positive culture (p = 0.01, hazard ratio = 1.4) and with
early age of onset of chronic P. aeruginosa infection (p = 0.004, hazard
ratio = 1.9). The risk was highest in individuals with less selective
bias toward a P. aeruginosa-negative history, i.e., children enrolled
before 1.5 years of age and 103 enrollees who participated in the study
despite a history of P. aeruginosa-positive cultures. No significant
interaction was found between CFTR genotypes and DCTN4 mutations,
although power to detect such an interaction was low.
*FIELD* RF
1. Ayalon, G.; Davis, J. Q.; Scotland, P. B.; Bennett, V.: An ankyrin-based
mechanism for functional organization of dystrophin and dystroglycan. Cell 135:
1189-1200, 2008.
2. Boultwood, J.; Fidler, C.; Strickson, A. J.; Watkins, F.; Kostrzewa,
M.; Jaju, R. J.; Muller, U.; Wainscoat, J. S.: Transcription mapping
of the 5q- syndrome critical region: cloning of two novel genes and
sequencing, expression, and mapping of a further six novel cDNAs. Genomics 66:
26-34, 2000.
3. Emond, M. J.; Louie, T.; Emerson, J.; Zhao, W.; Mathias, R. A.;
Knowles, M. R.; Wright, F. A.; Rieder, M. J.; Tabor, H. K.; Nickerson,
D. A.; Barnes, K. C.; National Heart, Lung, and Blood Institute (NHLBI)
GO Exome Sequencing Project; Lung GO; Gibson, R. L.; Bamshad, M.
J.: Exome sequencing of extreme phenotypes identifies DCTN4 as a
modifier of chronic Pseudomonas aeruginosa infection in cystic fibrosis. Nature
Genet. 44: 886-889, 2012.
4. Karki, S.; Tokito, M. K.; Holzbaur, E. L. F.: A dynactin subunit
with a highly conserved cysteine-rich motif interacts directly with
Arp1. J. Biol. Chem. 275: 4834-4839, 2000.
5. Lim, C. M.; Cater, M. A.; Mercer, J. F. B.; La Fontaine, S.: Copper-dependent
interaction of dynactin subunit p62 with the N terminus of ATP7B but
not ATP7A. J. Biol. Chem. 281: 14006-14014, 2006.
*FIELD* CN
Ada Hamosh - updated: 2/26/2013
*FIELD* CD
Patricia A. Hartz: 8/10/2012
*FIELD* ED
alopez: 03/04/2013
terry: 2/26/2013
mgross: 8/10/2012