Full text data of CUL3
CUL3
(KIAA0617)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Cullin-3; CUL-3
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Cullin-3; CUL-3
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00014312
IPI00014312 Splice Isoform 1 Of Cullin homolog 3 Involved in ubiquitination soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a nuclear and golgi isoform 1 or 2 expected molecular weight found in band found in band >188 kDa
IPI00014312 Splice Isoform 1 Of Cullin homolog 3 Involved in ubiquitination soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a nuclear and golgi isoform 1 or 2 expected molecular weight found in band found in band >188 kDa
UniProt
Q13618
ID CUL3_HUMAN Reviewed; 768 AA.
AC Q13618; A8K536; B8ZZC3; O75415; Q569L3; Q9UBI8; Q9UET7;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 24-JAN-2001, sequence version 2.
DT 22-JAN-2014, entry version 139.
DE RecName: Full=Cullin-3;
DE Short=CUL-3;
GN Name=CUL3; Synonyms=KIAA0617;
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).
RX PubMed=9733711; DOI=10.1074/jbc.273.38.24289;
RA Du M., Sansores-Garcia L., Zu Z., Wu K.K.;
RT "Cloning and expression analysis of a novel salicylate suppressible
RT gene, Hs-CUL-3, a member of cullin/Cdc53 family.";
RL J. Biol. Chem. 273:24289-24292(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=9734811; DOI=10.1093/dnares/5.3.169;
RA Ishikawa K., Nagase T., Suyama M., Miyajima N., Tanaka A., Kotani H.,
RA Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. X.
RT The complete sequences of 100 new cDNA clones from brain which can
RT code for large proteins in vitro.";
RL DNA Res. 5:169-176(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Colon carcinoma;
RX PubMed=9663463;
RA Michel J.J., Xiong Y.;
RT "Human CUL-1, but not other cullin family members, selectively
RT interacts with SKP1 to form a complex with SKP2 and cyclin A.";
RL Cell Growth Differ. 9:435-449(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RC TISSUE=Testis;
RA Xu M., Huang X.Y., Yin L.L., Xu Z.Y., Lu L., Zhou Z.M., Sha J.H.;
RT "Cloning and characterization of a new isoform of CUL3 gene in
RT testis.";
RL Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [7]
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Ovary, Skin, and Uterus;
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 [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 192-768.
RX PubMed=8681378; DOI=10.1016/S0092-8674(00)81267-2;
RA Kipreos E.T., Lander L.E., Wing J.P., He W.W., Hedgecock E.M.;
RT "cul-1 is required for cell cycle exit in C. elegans and identifies a
RT novel gene family.";
RL Cell 85:829-839(1996).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 398-768.
RC TISSUE=Brain;
RA Yu W., Sarginson J., Gibbs R.A.;
RL Submitted (MAR-1998) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP ALTERNATIVE SPLICING (ISOFORMS 1 AND 3), FUNCTION, SUBCELLULAR
RP LOCATION, INTERACTION WITH CYCE, AND NEDDYLATION.
RX PubMed=10500095; DOI=10.1101/gad.13.18.2375;
RA Singer J.D., Gurian-West M., Clurman B., Roberts J.M.;
RT "Cullin-3 targets cyclin E for ubiquitination and controls S phase in
RT mammalian cells.";
RL Genes Dev. 13:2375-2387(1999).
RN [12]
RP FUNCTION.
RX PubMed=11311237; DOI=10.1016/S0014-5793(01)02343-2;
RA Maeda I., Ohta T., Koizumi H., Fukuda M.;
RT "In vitro ubiquitination of cyclin D1 by ROC1-CUL1 and ROC1-CUL3.";
RL FEBS Lett. 494:181-185(2001).
RN [13]
RP NEDDYLATION.
RX PubMed=10597293; DOI=10.1038/sj.onc.1203093;
RA Hori T., Osaka F., Chiba T., Miyamoto C., Okabayashi K., Shimbara N.,
RA Kato S., Tanaka K.;
RT "Covalent modification of all members of human cullin family proteins
RT by NEDD8.";
RL Oncogene 18:6829-6834(1999).
RN [14]
RP INTERACTION WITH RBX1 AND RNF7.
RX PubMed=10230407; DOI=10.1016/S1097-2765(00)80482-7;
RA Ohta T., Michel J.J., Schottelius A.J., Xiong Y.;
RT "ROC1, a homolog of APC11, represents a family of cullin partners with
RT an associated ubiquitin ligase activity.";
RL Mol. Cell 3:535-541(1999).
RN [15]
RP INTERACTION WITH TIP120A.
RX PubMed=12609982; DOI=10.1074/jbc.M213070200;
RA Min K.-W., Hwang J.-W., Lee J.-S., Park Y., Tamura T.-A., Yoon J.-B.;
RT "TIP120A associates with cullins and modulates ubiquitin ligase
RT activity.";
RL J. Biol. Chem. 278:15905-15910(2003).
RN [16]
RP INTERACTION WITH GAN; ZBTB16; KLHL9; KLHL13; KLHL21; KLHL3; KLHL15;
RP KLHL20; KLHL36; GMCL1P1; BTBD1 AND SPOP.
RX PubMed=14528312; DOI=10.1038/ncb1056;
RA Furukawa M., He Y.J., Borchers C., Xiong Y.;
RT "Targeting of protein ubiquitination by BTB-Cullin 3-Roc1 ubiquitin
RT ligases.";
RL Nat. Cell Biol. 5:1001-1007(2003).
RN [17]
RP FUNCTION, IDENTIFICATION IN THE BCR(KLHL41) COMPLEX, IDENTIFICATION IN
RP THE BCR(ENC1) COMPLEX, IDENTIFICATION IN THE BCR(KEAP1) COMPLEX, AND
RP IDENTIFICATION IN THE BCR(GAN) COMPLEX.
RX PubMed=15983046; DOI=10.1074/jbc.M501279200;
RA Zhang D.D., Lo S.C., Sun Z., Habib G.M., Lieberman M.W., Hannink M.;
RT "Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein for
RT Cul3, targets Keap1 for degradation by a proteasome-independent
RT pathway.";
RL J. Biol. Chem. 280:30091-30099(2005).
RN [18]
RP IDENTIFICATION IN A COMPLEX WITH SPOP AND BMI1, IDENTIFICATION IN A
RP COMPLEX WITH SPOP AND H2AFY, AND FUNCTION.
RX PubMed=15897469; DOI=10.1073/pnas.0408918102;
RA Hernandez-Munoz I., Lund A.H., van der Stoop P., Boutsma E.,
RA Muijrers I., Verhoeven E., Nusinow D.A., Panning B., Marahrens Y.,
RA van Lohuizen M.;
RT "Stable X chromosome inactivation involves the PRC1 Polycomb complex
RT and requires histone MACROH2A1 and the CULLIN3/SPOP ubiquitin E3
RT ligase.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:7635-7640(2005).
RN [19]
RP IDENTIFICATION IN THE BCR(SPOP) COMPLEX, INTERACTION WITH SPOP, AND
RP FUNCTION IN UBIQUITINATION OF DAXX.
RX PubMed=16524876; DOI=10.1074/jbc.M600204200;
RA Kwon J.E., La M., Oh K.H., Oh Y.M., Kim G.R., Seol J.H., Baek S.H.,
RA Chiba T., Tanaka K., Bang O.S., Joe C.O., Chung C.H.;
RT "BTB domain-containing speckle-type POZ protein (SPOP) serves as an
RT adaptor of Daxx for ubiquitination by Cul3-based ubiquitin ligase.";
RL J. Biol. Chem. 281:12664-12672(2006).
RN [20]
RP FUNCTION, AND INTERACTION WITH KLHL9 AND KLHL13.
RX PubMed=17543862; DOI=10.1016/j.devcel.2007.03.019;
RA Sumara I., Quadroni M., Frei C., Olma M.H., Sumara G., Ricci R.,
RA Peter M.;
RT "A Cul3-based E3 ligase removes Aurora B from mitotic chromosomes,
RT regulating mitotic progression and completion of cytokinesis in human
RT cells.";
RL Dev. Cell 12:887-900(2007).
RN [21]
RP SELF-ASSOCIATION.
RX PubMed=17254749; DOI=10.1016/j.cellsig.2006.12.002;
RA Chew E.H., Poobalasingam T., Hawkey C.J., Hagen T.;
RT "Characterization of cullin-based E3 ubiquitin ligases in intact
RT mammalian cells -- evidence for cullin dimerization.";
RL Cell. Signal. 19:1071-1080(2007).
RN [22]
RP BCR COMPLEX HOMODIMERIZATION.
RX PubMed=17192413; DOI=10.1091/mbc.E06-06-0542;
RA Wimuttisuk W., Singer J.D.;
RT "The Cullin3 ubiquitin ligase functions as a Nedd8-bound
RT heterodimer.";
RL Mol. Biol. Cell 18:899-909(2007).
RN [23]
RP INTERACTION WITH KCTD5.
RX PubMed=18573101; DOI=10.1111/j.1742-4658.2008.06537.x;
RA Bayon Y., Trinidad A.G., de la Puerta M.L., Del Carmen Rodriguez M.,
RA Bogetz J., Rojas A., De Pereda J.M., Rahmouni S., Williams S.,
RA Matsuzawa S., Reed J.C., Crespo M.S., Mustelin T., Alonso A.;
RT "KCTD5, a putative substrate adaptor for cullin3 ubiquitin ligases.";
RL FEBS J. 275:3900-3910(2008).
RN [24]
RP FUNCTION, AND INTERACTION WITH ATF2 AND KAT5.
RX PubMed=18397884; DOI=10.1074/jbc.M802030200;
RA Bhoumik A., Singha N., O'Connell M.J., Ronai Z.A.;
RT "Regulation of TIP60 by ATF2 modulates ATM activation.";
RL J. Biol. Chem. 283:17605-17614(2008).
RN [25]
RP IDENTIFICATION IN THE BCR(KLHL42) COMPLEX, FUNCTION IN UBIQUITINATION
RP OF KATNA1, AND INTERACTION WITH KATNA1 AND KLHL42.
RX PubMed=19261606; DOI=10.1074/jbc.M809374200;
RA Cummings C.M., Bentley C.A., Perdue S.A., Baas P.W., Singer J.D.;
RT "The Cul3/Klhdc5 E3 ligase regulates p60/katanin and is required for
RT normal mitosis in mammalian cells.";
RL J. Biol. Chem. 284:11663-11675(2009).
RN [26]
RP IDENTIFICATION IN THE BCR(KLHL21) COMPLEX, AND FUNCTION.
RX PubMed=19995937; DOI=10.1083/jcb.200906117;
RA Maerki S., Olma M.H., Staubli T., Steigemann P., Gerlich D.W.,
RA Quadroni M., Sumara I., Peter M.;
RT "The Cul3-KLHL21 E3 ubiquitin ligase targets aurora B to midzone
RT microtubules in anaphase and is required for cytokinesis.";
RL J. Cell Biol. 187:791-800(2009).
RN [27]
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 [28]
RP FUNCTION, SUBCELLULAR LOCATION, AND IDENTIFICATION IN A COMPLEX WITH
RP SPOP AND BRMS1.
RX PubMed=22085717; DOI=10.1016/j.bbrc.2011.10.154;
RA Kim B., Nam H.J., Pyo K.E., Jang M.J., Kim I.S., Kim D., Boo K.,
RA Lee S.H., Yoon J.B., Baek S.H., Kim J.H.;
RT "Breast cancer metastasis suppressor 1 (BRMS1) is destabilized by the
RT Cul3-SPOP E3 ubiquitin ligase complex.";
RL Biochem. Biophys. Res. Commun. 415:720-726(2011).
RN [29]
RP INTERACTION WITH KCTD7.
RX PubMed=22748208; DOI=10.1016/j.ajhg.2012.05.023;
RA Staropoli J.F., Karaa A., Lim E.T., Kirby A., Elbalalesy N.,
RA Romansky S.G., Leydiker K.B., Coppel S.H., Barone R., Xin W.,
RA MacDonald M.E., Abdenur J.E., Daly M.J., Sims K.B., Cotman S.L.;
RT "A homozygous mutation in KCTD7 links neuronal ceroid lipofuscinosis
RT to the ubiquitin-proteasome system.";
RL Am. J. Hum. Genet. 91:202-208(2012).
RN [30]
RP IDENTIFICATION IN THE BCR(KLHL25) COMPLEX, AND FUNCTION.
RX PubMed=22578813; DOI=10.1016/j.molcel.2012.04.004;
RA Yanagiya A., Suyama E., Adachi H., Svitkin Y.V., Aza-Blanc P.,
RA Imataka H., Mikami S., Martineau Y., Ronai Z.A., Sonenberg N.;
RT "Translational homeostasis via the mRNA cap-binding protein, eIF4E.";
RL Mol. Cell 46:847-858(2012).
RN [31]
RP IDENTIFICATION IN THE BCR(KLHL12) COMPLEX, AND FUNCTION.
RX PubMed=22358839; DOI=10.1038/nature10822;
RA Jin L., Pahuja K.B., Wickliffe K.E., Gorur A., Baumgartel C.,
RA Schekman R., Rape M.;
RT "Ubiquitin-dependent regulation of COPII coat size and function.";
RL Nature 482:495-500(2012).
RN [32]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
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).
RN [33]
RP FUNCTION, AND INTERACTION WITH KLHL3.
RX PubMed=23387299; DOI=10.1042/BJ20121903;
RA Ohta A., Schumacher F.R., Mehellou Y., Johnson C., Knebel A.,
RA Macartney T.J., Wood N.T., Alessi D.R., Kurz T.;
RT "The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension
RT syndrome interacts with and ubiquitylates WNK isoforms: disease-
RT causing mutations in KLHL3 and WNK4 disrupt interaction.";
RL Biochem. J. 451:111-122(2013).
RN [34]
RP FUNCTION, AND IDENTIFICATION IN THE BCR(KLHL3) COMPLEX.
RX PubMed=23453970; DOI=10.1016/j.celrep.2013.02.024;
RA Wakabayashi M., Mori T., Isobe K., Sohara E., Susa K., Araki Y.,
RA Chiga M., Kikuchi E., Nomura N., Mori Y., Matsuo H., Murata T.,
RA Nomura S., Asano T., Kawaguchi H., Nonoyama S., Rai T., Sasaki S.,
RA Uchida S.;
RT "Impaired KLHL3-mediated ubiquitination of WNK4 causes human
RT hypertension.";
RL Cell Rep. 3:858-868(2013).
RN [35]
RP IDENTIFICATION IN THE BCR(KLHL22) COMPLEX, AND FUNCTION.
RX PubMed=23455478; DOI=10.1038/ncb2695;
RA Beck J., Maerki S., Posch M., Metzger T., Persaud A., Scheel H.,
RA Hofmann K., Rotin D., Pedrioli P., Swedlow J.R., Peter M., Sumara I.;
RT "Ubiquitylation-dependent localization of PLK1 in mitosis.";
RL Nat. Cell Biol. 15:430-439(2013).
RN [36]
RP FUNCTION, AND IDENTIFICATION IN THE BCR(KLHL3) COMPLEX.
RX PubMed=23576762; DOI=10.1073/pnas.1304592110;
RA Shibata S., Zhang J., Puthumana J., Stone K.L., Lifton R.P.;
RT "Kelch-like 3 and Cullin 3 regulate electrolyte homeostasis via
RT ubiquitination and degradation of WNK4.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:7838-7843(2013).
RN [37]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 20-381 IN COMPLEX WITH SPOP,
RP FUNCTION, IDENTIFICATION IN UBIQUITIN LIGASE COMPLEXES WITH SPOP AND
RP SPOPL, AND SUBUNIT.
RX PubMed=22632832; DOI=10.1016/j.str.2012.04.009;
RA Errington W.J., Khan M.Q., Bueler S.A., Rubinstein J.L.,
RA Chakrabartty A., Prive G.G.;
RT "Adaptor protein self-assembly drives the control of a cullin-RING
RT ubiquitin ligase.";
RL Structure 20:1141-1153(2012).
RN [38]
RP X-RAY CRYSTALLOGRAPHY (3.51 ANGSTROMS) OF 20-381 IN COMPLEX WITH
RP KLHL3.
RX PubMed=23573258; DOI=10.1371/journal.pone.0060445;
RA Ji A.X., Prive G.G.;
RT "Crystal structure of KLHL3 in complex with Cullin3.";
RL PLoS ONE 8:E60445-E60445(2013).
RN [39]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 1-388 IN COMPLEX WITH KLHL11,
RP AND INTERACTION WITH KLHL11.
RX PubMed=23349464; DOI=10.1074/jbc.M112.437996;
RA Canning P., Cooper C.D., Krojer T., Murray J.W., Pike A.C.,
RA Chaikuad A., Keates T., Thangaratnarajah C., Hojzan V., Marsden B.D.,
RA Gileadi O., Knapp S., von Delft F., Bullock A.N.;
RT "Structural basis for Cul3 assembly with the BTB-Kelch family of E3
RT ubiquitin ligases.";
RL J. Biol. Chem. 288:7803-7814(2013).
RN [40]
RP VARIANTS PHA2E GLY-413 AND ARG-459.
RX PubMed=22266938; DOI=10.1038/nature10814;
RA Boyden L.M., Choi M., Choate K.A., Nelson-Williams C.J., Farhi A.,
RA Toka H.R., Tikhonova I.R., Bjornson R., Mane S.M., Colussi G.,
RA Lebel M., Gordon R.D., Semmekrot B.A., Poujol A., Valimaki M.J.,
RA De Ferrari M.E., Sanjad S.A., Gutkin M., Karet F.E., Tucci J.R.,
RA Stockigt J.R., Keppler-Noreuil K.M., Porter C.C., Anand S.K.,
RA Whiteford M.L., Davis I.D., Dewar S.B., Bettinelli A., Fadrowski J.J.,
RA Belsha C.W., Hunley T.E., Nelson R.D., Trachtman H., Cole T.R.,
RA Pinsk M., Bockenhauer D., Shenoy M., Vaidyanathan P., Foreman J.W.,
RA Rasoulpour M., Thameem F., Al-Shahrouri H.Z., Radhakrishnan J.,
RA Gharavi A.G., Goilav B., Lifton R.P.;
RT "Mutations in kelch-like 3 and cullin 3 cause hypertension and
RT electrolyte abnormalities.";
RL Nature 482:98-102(2012).
CC -!- FUNCTION: Core component of multiple cullin-RING-based BCR (BTB-
CC CUL3-RBX1) E3 ubiquitin-protein ligase complexes which mediate the
CC ubiquitination and subsequent proteasomal degradation of target
CC proteins. As a scaffold protein may contribute to catalysis
CC through positioning of the substrate and the ubiquitin-conjugating
CC enzyme. The E3 ubiquitin-protein ligase activity of the complex is
CC dependent on the neddylation of the cullin subunit and is
CC inhibited by the association of the deneddylated cullin subunit
CC with TIP120A/CAND1 (By similarity). The functional specificity of
CC the BCR complex depends on the BTB domain-containing protein as
CC the substrate recognition component. BCR(KLHL42) is involved in
CC ubiquitination of KATNA1. BCR(SPOP) is involved in ubiquitination
CC of BMI1/PCGF4, BRMS1, H2AFY and DAXX, GLI2 and GLI3. Can also form
CC a cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein
CC ligase complex containing homodimeric SPOPL or the heterodimer
CC formed by SPOP and SPOPL; these complexes have lower ubiquitin
CC ligase activity. BCR(KLHL9-KLHL13) controls the dynamic behavior
CC of AURKB on mitotic chromosomes and thereby coordinates faithful
CC mitotic progression and completion of cytokinesis. BCR(KLHL12) is
CC involved in ER-Golgi transport by regulating the size of COPII
CC coats, thereby playing a key role in collagen export, which is
CC required for embryonic stem (ES) cells division: BCR(KLHL12) acts
CC by mediating monoubiquitination of SEC31 (SEC31A or SEC31B).
CC BCR(KLHL3) acts as a regulator of ion transport in the distal
CC nephron; by mediating ubiquitination of WNK4. The BCR(KLHL21) E3
CC ubiquitin ligase complex regulates localization of the chromosomal
CC passenger complex (CPC) from chromosomes to the spindle midzone in
CC anaphase and mediates the ubiquitination of AURKB. The BCR(KLHL22)
CC ubiquitin ligase complex mediates monoubiquitination of PLK1,
CC leading to PLK1 dissociation from phosphoreceptor proteins and
CC subsequent removal from kinetochores, allowing silencing of the
CC spindle assembly checkpoint (SAC) and chromosome segregation. The
CC BCR(KLHL25) ubiquitin ligase complex is involved in translational
CC homeostasis by mediating ubiquitination and subsequent degradation
CC of hypophosphorylated EIF4EBP1 (4E-BP1). Involved in
CC ubiquitination of cyclin E and of cyclin D1 (in vitro) thus
CC involved in regulation of G1/S transition. Involved in the
CC ubiquitination of KEAP1, ENC1 and KLHL41. In concert with ATF2 and
CC RBX1, promotes degradation of KAT5 thereby attenuating its ability
CC to acetylate and activate ATM.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Forms neddylation-dependent homodimers. Component of
CC multiple BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes
CC formed of CUL3, RBX1 and a variable BTB domain-containing protein
CC acting as both, adapter to cullin and substrate recognition
CC subunit. The BCR complex may be active as a heterodimeric complex,
CC in which NEDD8, covalently attached to one CUL3 molecule, binds to
CC the C-terminus of a second CUL3 molecule. Interacts with RBX1,
CC RNF7, CYCE and TIP120A/CAND1. Part of the BCR(SPOP) containing
CC SPOP, and of BCR containing homodimeric SPOPL or the heterodimer
CC formed by SPOP and SPOPL. Part of the probable BCR(KLHL9-KLHL13)
CC complex with BTB domain proteins KLHL9 and KLHL13. Part of the
CC BCR(KLHL41) complex containing KLHL41. Component of the
CC BCR(KLHL12) E3 ubiquitin ligase complex, at least composed of CUL3
CC and KLHL12 and RBX1. Component of the BCR(KLHL3) E3 ubiquitin
CC ligase complex, at least composed of CUL3 and KLHL3 and RBX1
CC (Probable). Part of the BCR(ENC1) complex containing ENC1. Part of
CC a complex consisting of BMI1/PCGF4, CUL3 and SPOP. Part of a
CC complex consisting of BRMS1, CUL3 and SPOP. Component of the
CC BCR(KLHL21) E3 ubiquitin ligase complex, at least composed of
CC CUL3, KLHL21 and RBX1. Component of the BCR(KLHL22) E3 ubiquitin
CC ligase complex, at least composed of CUL3, KLHL22 and RBX1.
CC Component of the BCR(KLHL25) E3 ubiquitin ligase complex, at least
CC composed of CUL3, KLHL25 and RBX1. Part of a complex consisting of
CC H2AFY, CUL3 and SPOP. Component of the BCR(KLHL42) E3 ubiquitin
CC ligase complex, at least composed of CUL3 and KLHL42. Interacts
CC with KLHL42 (via the BTB domain). Interacts with KATNA1; the
CC interaction is enhanced by KLHL42. Interacts with KCTD5, KLHL9,
CC KLHL11, KLHL13, GAN, ZBTB16, KLHL3, KLHL15, KLHL20, KLHL36,
CC GMCL1P1, BTBD1. Part of a complex that contains CUL3, RBX1 and
CC GAN. Interacts (via BTB domain) with KLHL17; the interaction
CC regulates surface GRIK2 expression. Interacts with KCTD7. Part of
CC the BCR(GAN) complex containing GAN. Part of the BCR(KEAP1)
CC complex containing KEAP1. Interacts with KLHL10 (By similarity).
CC Interacts with KAT5 and ATF2.
CC -!- INTERACTION:
CC Q86VP6:CAND1; NbExp=2; IntAct=EBI-456129, EBI-456077;
CC Q14790:CASP8; NbExp=6; IntAct=EBI-456129, EBI-78060;
CC P08238:HSP90AB1; NbExp=2; IntAct=EBI-456129, EBI-352572;
CC Q9Y2M5:KLHL20; NbExp=2; IntAct=EBI-456129, EBI-7904035;
CC O43791:SPOP; NbExp=2; IntAct=EBI-456129, EBI-743549;
CC P50591:TNFSF10; NbExp=2; IntAct=EBI-456129, EBI-495373;
CC -!- SUBCELLULAR LOCATION: Nucleus. Golgi apparatus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=Cul-3 Long;
CC IsoId=Q13618-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q13618-2; Sequence=VSP_008824;
CC Name=3; Synonyms=Cul-3 Short;
CC IsoId=Q13618-3; Sequence=VSP_008825;
CC -!- TISSUE SPECIFICITY: Widely expressed.
CC -!- PTM: Neddylated. Attachment of NEDD8 is required for the E3
CC ubiquitin-protein ligase activity of the BCR complex. Deneddylated
CC via its interaction with the COP9 signalosome (CSN) complex.
CC -!- DISEASE: Pseudohypoaldosteronism 2E (PHA2E) [MIM:614496]: An
CC autosomal dominant disorder characterized by severe hypertension,
CC hyperkalemia, hyperchloremia, hyperchloremic metabolic acidosis,
CC and correction of physiologic abnormalities by thiazide diuretics.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the cullin family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAC28621.1; Type=Frameshift; Positions=452;
CC Sequence=AAC36682.1; Type=Frameshift; Positions=159, 179;
CC Sequence=BAA31592.2; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AF064087; AAC36304.1; -; mRNA.
DR EMBL; AB014517; BAA31592.2; ALT_INIT; mRNA.
DR EMBL; AF062537; AAC36682.1; ALT_FRAME; mRNA.
DR EMBL; AY337761; AAQ01660.1; -; mRNA.
DR EMBL; AK291151; BAF83840.1; -; mRNA.
DR EMBL; AC073052; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC092679; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471063; EAW70828.1; -; Genomic_DNA.
DR EMBL; BC031844; AAH31844.1; -; mRNA.
DR EMBL; BC039598; AAH39598.1; -; mRNA.
DR EMBL; BC092409; AAH92409.1; -; mRNA.
DR EMBL; U58089; AAC50546.1; -; mRNA.
DR EMBL; AF052147; AAC28621.1; ALT_FRAME; mRNA.
DR RefSeq; NP_001244126.1; NM_001257197.1.
DR RefSeq; NP_001244127.1; NM_001257198.1.
DR RefSeq; NP_003581.1; NM_003590.4.
DR UniGene; Hs.372286; -.
DR PDB; 4AP2; X-ray; 2.80 A; B=1-388.
DR PDB; 4APF; X-ray; 3.10 A; B=23-388.
DR PDB; 4EOZ; X-ray; 2.40 A; B/D=20-381.
DR PDB; 4HXI; X-ray; 3.51 A; B=20-381.
DR PDBsum; 4AP2; -.
DR PDBsum; 4APF; -.
DR PDBsum; 4EOZ; -.
DR PDBsum; 4HXI; -.
DR ProteinModelPortal; Q13618; -.
DR SMR; Q13618; 17-768.
DR DIP; DIP-31611N; -.
DR IntAct; Q13618; 38.
DR MINT; MINT-3028280; -.
DR STRING; 9606.ENSP00000264414; -.
DR PhosphoSite; Q13618; -.
DR DMDM; 12643396; -.
DR PaxDb; Q13618; -.
DR PRIDE; Q13618; -.
DR Ensembl; ENST00000264414; ENSP00000264414; ENSG00000036257.
DR Ensembl; ENST00000344951; ENSP00000343601; ENSG00000036257.
DR Ensembl; ENST00000409096; ENSP00000387200; ENSG00000036257.
DR Ensembl; ENST00000409777; ENSP00000386525; ENSG00000036257.
DR GeneID; 8452; -.
DR KEGG; hsa:8452; -.
DR UCSC; uc002vny.3; human.
DR CTD; 8452; -.
DR GeneCards; GC02M225298; -.
DR HGNC; HGNC:2553; CUL3.
DR HPA; CAB002678; -.
DR MIM; 603136; gene.
DR MIM; 614496; phenotype.
DR neXtProt; NX_Q13618; -.
DR Orphanet; 300530; Pseudohypoaldosteronism type 2E.
DR PharmGKB; PA27049; -.
DR eggNOG; COG5647; -.
DR HOVERGEN; HBG003619; -.
DR InParanoid; Q13618; -.
DR KO; K03869; -.
DR OMA; IHTKNAS; -.
DR OrthoDB; EOG7C5M7H; -.
DR PhylomeDB; Q13618; -.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; Q13618; -.
DR UniPathway; UPA00143; -.
DR ChiTaRS; CUL3; human.
DR GeneWiki; CUL3; -.
DR GenomeRNAi; 8452; -.
DR NextBio; 31630; -.
DR PRO; PR:Q13618; -.
DR ArrayExpress; Q13618; -.
DR Bgee; Q13618; -.
DR CleanEx; HS_CUL3; -.
DR Genevestigator; Q13618; -.
DR GO; GO:0031463; C:Cul3-RING ubiquitin ligase complex; IDA:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005827; C:polar microtubule; IDA:UniProtKB.
DR GO; GO:0031208; F:POZ domain binding; IDA:UniProtKB.
DR GO; GO:0007050; P:cell cycle arrest; TAS:ProtInc.
DR GO; GO:0016477; P:cell migration; IMP:UniProtKB.
DR GO; GO:0048208; P:COPII vesicle coating; IMP:UniProtKB.
DR GO; GO:0008054; P:cyclin catabolic process; IDA:MGI.
DR GO; GO:0000910; P:cytokinesis; IMP:UniProtKB.
DR GO; GO:0040016; P:embryonic cleavage; ISS:UniProtKB.
DR GO; GO:0000082; P:G1/S transition of mitotic cell cycle; TAS:ProtInc.
DR GO; GO:0007369; P:gastrulation; IEA:Ensembl.
DR GO; GO:0007229; P:integrin-mediated signaling pathway; ISS:UniProtKB.
DR GO; GO:0097193; P:intrinsic apoptotic signaling pathway; TAS:ProtInc.
DR GO; GO:0000090; P:mitotic anaphase; IMP:UniProtKB.
DR GO; GO:0035024; P:negative regulation of Rho protein signal transduction; IMP:UniProtKB.
DR GO; GO:0008284; P:positive regulation of cell proliferation; TAS:ProtInc.
DR GO; GO:0032467; P:positive regulation of cytokinesis; IMP:UniProtKB.
DR GO; GO:0006513; P:protein monoubiquitination; IDA:UniProtKB.
DR GO; GO:0000209; P:protein polyubiquitination; IDA:UniProtKB.
DR GO; GO:0017145; P:stem cell division; ISS:UniProtKB.
DR GO; GO:0043149; P:stress fiber assembly; IMP:UniProtKB.
DR GO; GO:0001831; P:trophectodermal cellular morphogenesis; IEA:Ensembl.
DR GO; GO:0016055; P:Wnt receptor signaling pathway; IEA:Ensembl.
DR Gene3D; 1.10.10.10; -; 2.
DR InterPro; IPR016157; Cullin_CS.
DR InterPro; IPR016158; Cullin_homology.
DR InterPro; IPR001373; Cullin_N.
DR InterPro; IPR019559; Cullin_neddylation_domain.
DR InterPro; IPR016159; Cullin_repeat-like_dom.
DR InterPro; IPR011991; WHTH_DNA-bd_dom.
DR Pfam; PF00888; Cullin; 1.
DR Pfam; PF10557; Cullin_Nedd8; 1.
DR SMART; SM00182; CULLIN; 1.
DR SMART; SM00884; Cullin_Nedd8; 1.
DR SUPFAM; SSF74788; SSF74788; 1.
DR SUPFAM; SSF75632; SSF75632; 1.
DR PROSITE; PS01256; CULLIN_1; 1.
DR PROSITE; PS50069; CULLIN_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Disease mutation; ER-Golgi transport; Golgi apparatus;
KW Isopeptide bond; Nucleus; Polymorphism; Reference proteome; Transport;
KW Ubl conjugation; Ubl conjugation pathway.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 768 Cullin-3.
FT /FTId=PRO_0000119793.
FT MOD_RES 2 2 N-acetylserine.
FT CROSSLNK 712 712 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in NEDD8) (By
FT similarity).
FT VAR_SEQ 1 24 Missing (in isoform 2).
FT /FTId=VSP_008824.
FT VAR_SEQ 23 88 Missing (in isoform 3).
FT /FTId=VSP_008825.
FT VARIANT 13 13 D -> H (in dbSNP:rs2969802).
FT /FTId=VAR_017194.
FT VARIANT 184 184 R -> S (in dbSNP:rs17480168).
FT /FTId=VAR_048839.
FT VARIANT 413 413 D -> G (in PHA2E).
FT /FTId=VAR_067532.
FT VARIANT 459 459 K -> R (in PHA2E).
FT /FTId=VAR_067533.
FT VARIANT 567 567 V -> I (in dbSNP:rs3738952).
FT /FTId=VAR_017195.
FT CONFLICT 13 13 D -> G (in Ref. 3; AAC36682).
FT CONFLICT 397 397 K -> T (in Ref. 4; AAQ01660).
FT CONFLICT 481 481 N -> T (in Ref. 4; AAQ01660).
FT CONFLICT 609 609 E -> G (in Ref. 8; AAH31844).
FT CONFLICT 666 666 T -> I (in Ref. 4; AAQ01660).
FT HELIX 26 45
FT HELIX 49 51
FT HELIX 54 66
FT HELIX 70 87
FT HELIX 89 94
FT TURN 95 98
FT HELIX 101 122
FT HELIX 124 129
FT HELIX 132 134
FT HELIX 139 150
FT TURN 151 153
FT HELIX 155 173
FT HELIX 180 192
FT STRAND 195 198
FT HELIX 199 204
FT HELIX 206 227
FT HELIX 230 251
FT HELIX 254 256
FT HELIX 257 268
FT TURN 269 272
FT HELIX 273 277
FT TURN 280 282
FT HELIX 284 287
FT TURN 288 291
FT HELIX 293 303
FT HELIX 309 323
FT HELIX 339 358
FT HELIX 364 380
SQ SEQUENCE 768 AA; 88930 MW; A1A02022480BF099 CRC64;
MSNLSKGTGS RKDTKMRIRA FPMTMDEKYV NSIWDLLKNA IQEIQRKNNS GLSFEELYRN
AYTMVLHKHG EKLYTGLREV VTEHLINKVR EDVLNSLNNN FLQTLNQAWN DHQTAMVMIR
DILMYMDRVY VQQNNVENVY NLGLIIFRDQ VVRYGCIRDH LRQTLLDMIA RERKGEVVDR
GAIRNACQML MILGLEGRSV YEEDFEAPFL EMSAEFFQME SQKFLAENSA SVYIKKVEAR
INEEIERVMH CLDKSTEEPI VKVVERELIS KHMKTIVEME NSGLVHMLKN GKTEDLGCMY
KLFSRVPNGL KTMCECMSSY LREQGKALVS EEGEGKNPVD YIQGLLDLKS RFDRFLLESF
NNDRLFKQTI AGDFEYFLNL NSRSPEYLSL FIDDKLKKGV KGLTEQEVET ILDKAMVLFR
FMQEKDVFER YYKQHLARRL LTNKSVSDDS EKNMISKLKT ECGCQFTSKL EGMFRDMSIS
NTTMDEFRQH LQATGVSLGG VDLTVRVLTT GYWPTQSATP KCNIPPAPRH AFEIFRRFYL
AKHSGRQLTL QHHMGSADLN ATFYGPVKKE DGSEVGVGGA QVTGSNTRKH ILQVSTFQMT
ILMLFNNREK YTFEEIQQET DIPERELVRA LQSLACGKPT QRVLTKEPKS KEIENGHIFT
VNDQFTSKLH RVKIQTVAAK QGESDPERKE TRQKVDDDRK HEIEAAIVRI MKSRKKMQHN
VLVAEVTQQL KARFLPSPVV IKKRIEGLIE REYLARTPED RKVYTYVA
//
ID CUL3_HUMAN Reviewed; 768 AA.
AC Q13618; A8K536; B8ZZC3; O75415; Q569L3; Q9UBI8; Q9UET7;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 24-JAN-2001, sequence version 2.
DT 22-JAN-2014, entry version 139.
DE RecName: Full=Cullin-3;
DE Short=CUL-3;
GN Name=CUL3; Synonyms=KIAA0617;
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).
RX PubMed=9733711; DOI=10.1074/jbc.273.38.24289;
RA Du M., Sansores-Garcia L., Zu Z., Wu K.K.;
RT "Cloning and expression analysis of a novel salicylate suppressible
RT gene, Hs-CUL-3, a member of cullin/Cdc53 family.";
RL J. Biol. Chem. 273:24289-24292(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=9734811; DOI=10.1093/dnares/5.3.169;
RA Ishikawa K., Nagase T., Suyama M., Miyajima N., Tanaka A., Kotani H.,
RA Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. X.
RT The complete sequences of 100 new cDNA clones from brain which can
RT code for large proteins in vitro.";
RL DNA Res. 5:169-176(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Colon carcinoma;
RX PubMed=9663463;
RA Michel J.J., Xiong Y.;
RT "Human CUL-1, but not other cullin family members, selectively
RT interacts with SKP1 to form a complex with SKP2 and cyclin A.";
RL Cell Growth Differ. 9:435-449(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RC TISSUE=Testis;
RA Xu M., Huang X.Y., Yin L.L., Xu Z.Y., Lu L., Zhou Z.M., Sha J.H.;
RT "Cloning and characterization of a new isoform of CUL3 gene in
RT testis.";
RL Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [7]
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Ovary, Skin, and Uterus;
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 [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 192-768.
RX PubMed=8681378; DOI=10.1016/S0092-8674(00)81267-2;
RA Kipreos E.T., Lander L.E., Wing J.P., He W.W., Hedgecock E.M.;
RT "cul-1 is required for cell cycle exit in C. elegans and identifies a
RT novel gene family.";
RL Cell 85:829-839(1996).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 398-768.
RC TISSUE=Brain;
RA Yu W., Sarginson J., Gibbs R.A.;
RL Submitted (MAR-1998) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP ALTERNATIVE SPLICING (ISOFORMS 1 AND 3), FUNCTION, SUBCELLULAR
RP LOCATION, INTERACTION WITH CYCE, AND NEDDYLATION.
RX PubMed=10500095; DOI=10.1101/gad.13.18.2375;
RA Singer J.D., Gurian-West M., Clurman B., Roberts J.M.;
RT "Cullin-3 targets cyclin E for ubiquitination and controls S phase in
RT mammalian cells.";
RL Genes Dev. 13:2375-2387(1999).
RN [12]
RP FUNCTION.
RX PubMed=11311237; DOI=10.1016/S0014-5793(01)02343-2;
RA Maeda I., Ohta T., Koizumi H., Fukuda M.;
RT "In vitro ubiquitination of cyclin D1 by ROC1-CUL1 and ROC1-CUL3.";
RL FEBS Lett. 494:181-185(2001).
RN [13]
RP NEDDYLATION.
RX PubMed=10597293; DOI=10.1038/sj.onc.1203093;
RA Hori T., Osaka F., Chiba T., Miyamoto C., Okabayashi K., Shimbara N.,
RA Kato S., Tanaka K.;
RT "Covalent modification of all members of human cullin family proteins
RT by NEDD8.";
RL Oncogene 18:6829-6834(1999).
RN [14]
RP INTERACTION WITH RBX1 AND RNF7.
RX PubMed=10230407; DOI=10.1016/S1097-2765(00)80482-7;
RA Ohta T., Michel J.J., Schottelius A.J., Xiong Y.;
RT "ROC1, a homolog of APC11, represents a family of cullin partners with
RT an associated ubiquitin ligase activity.";
RL Mol. Cell 3:535-541(1999).
RN [15]
RP INTERACTION WITH TIP120A.
RX PubMed=12609982; DOI=10.1074/jbc.M213070200;
RA Min K.-W., Hwang J.-W., Lee J.-S., Park Y., Tamura T.-A., Yoon J.-B.;
RT "TIP120A associates with cullins and modulates ubiquitin ligase
RT activity.";
RL J. Biol. Chem. 278:15905-15910(2003).
RN [16]
RP INTERACTION WITH GAN; ZBTB16; KLHL9; KLHL13; KLHL21; KLHL3; KLHL15;
RP KLHL20; KLHL36; GMCL1P1; BTBD1 AND SPOP.
RX PubMed=14528312; DOI=10.1038/ncb1056;
RA Furukawa M., He Y.J., Borchers C., Xiong Y.;
RT "Targeting of protein ubiquitination by BTB-Cullin 3-Roc1 ubiquitin
RT ligases.";
RL Nat. Cell Biol. 5:1001-1007(2003).
RN [17]
RP FUNCTION, IDENTIFICATION IN THE BCR(KLHL41) COMPLEX, IDENTIFICATION IN
RP THE BCR(ENC1) COMPLEX, IDENTIFICATION IN THE BCR(KEAP1) COMPLEX, AND
RP IDENTIFICATION IN THE BCR(GAN) COMPLEX.
RX PubMed=15983046; DOI=10.1074/jbc.M501279200;
RA Zhang D.D., Lo S.C., Sun Z., Habib G.M., Lieberman M.W., Hannink M.;
RT "Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein for
RT Cul3, targets Keap1 for degradation by a proteasome-independent
RT pathway.";
RL J. Biol. Chem. 280:30091-30099(2005).
RN [18]
RP IDENTIFICATION IN A COMPLEX WITH SPOP AND BMI1, IDENTIFICATION IN A
RP COMPLEX WITH SPOP AND H2AFY, AND FUNCTION.
RX PubMed=15897469; DOI=10.1073/pnas.0408918102;
RA Hernandez-Munoz I., Lund A.H., van der Stoop P., Boutsma E.,
RA Muijrers I., Verhoeven E., Nusinow D.A., Panning B., Marahrens Y.,
RA van Lohuizen M.;
RT "Stable X chromosome inactivation involves the PRC1 Polycomb complex
RT and requires histone MACROH2A1 and the CULLIN3/SPOP ubiquitin E3
RT ligase.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:7635-7640(2005).
RN [19]
RP IDENTIFICATION IN THE BCR(SPOP) COMPLEX, INTERACTION WITH SPOP, AND
RP FUNCTION IN UBIQUITINATION OF DAXX.
RX PubMed=16524876; DOI=10.1074/jbc.M600204200;
RA Kwon J.E., La M., Oh K.H., Oh Y.M., Kim G.R., Seol J.H., Baek S.H.,
RA Chiba T., Tanaka K., Bang O.S., Joe C.O., Chung C.H.;
RT "BTB domain-containing speckle-type POZ protein (SPOP) serves as an
RT adaptor of Daxx for ubiquitination by Cul3-based ubiquitin ligase.";
RL J. Biol. Chem. 281:12664-12672(2006).
RN [20]
RP FUNCTION, AND INTERACTION WITH KLHL9 AND KLHL13.
RX PubMed=17543862; DOI=10.1016/j.devcel.2007.03.019;
RA Sumara I., Quadroni M., Frei C., Olma M.H., Sumara G., Ricci R.,
RA Peter M.;
RT "A Cul3-based E3 ligase removes Aurora B from mitotic chromosomes,
RT regulating mitotic progression and completion of cytokinesis in human
RT cells.";
RL Dev. Cell 12:887-900(2007).
RN [21]
RP SELF-ASSOCIATION.
RX PubMed=17254749; DOI=10.1016/j.cellsig.2006.12.002;
RA Chew E.H., Poobalasingam T., Hawkey C.J., Hagen T.;
RT "Characterization of cullin-based E3 ubiquitin ligases in intact
RT mammalian cells -- evidence for cullin dimerization.";
RL Cell. Signal. 19:1071-1080(2007).
RN [22]
RP BCR COMPLEX HOMODIMERIZATION.
RX PubMed=17192413; DOI=10.1091/mbc.E06-06-0542;
RA Wimuttisuk W., Singer J.D.;
RT "The Cullin3 ubiquitin ligase functions as a Nedd8-bound
RT heterodimer.";
RL Mol. Biol. Cell 18:899-909(2007).
RN [23]
RP INTERACTION WITH KCTD5.
RX PubMed=18573101; DOI=10.1111/j.1742-4658.2008.06537.x;
RA Bayon Y., Trinidad A.G., de la Puerta M.L., Del Carmen Rodriguez M.,
RA Bogetz J., Rojas A., De Pereda J.M., Rahmouni S., Williams S.,
RA Matsuzawa S., Reed J.C., Crespo M.S., Mustelin T., Alonso A.;
RT "KCTD5, a putative substrate adaptor for cullin3 ubiquitin ligases.";
RL FEBS J. 275:3900-3910(2008).
RN [24]
RP FUNCTION, AND INTERACTION WITH ATF2 AND KAT5.
RX PubMed=18397884; DOI=10.1074/jbc.M802030200;
RA Bhoumik A., Singha N., O'Connell M.J., Ronai Z.A.;
RT "Regulation of TIP60 by ATF2 modulates ATM activation.";
RL J. Biol. Chem. 283:17605-17614(2008).
RN [25]
RP IDENTIFICATION IN THE BCR(KLHL42) COMPLEX, FUNCTION IN UBIQUITINATION
RP OF KATNA1, AND INTERACTION WITH KATNA1 AND KLHL42.
RX PubMed=19261606; DOI=10.1074/jbc.M809374200;
RA Cummings C.M., Bentley C.A., Perdue S.A., Baas P.W., Singer J.D.;
RT "The Cul3/Klhdc5 E3 ligase regulates p60/katanin and is required for
RT normal mitosis in mammalian cells.";
RL J. Biol. Chem. 284:11663-11675(2009).
RN [26]
RP IDENTIFICATION IN THE BCR(KLHL21) COMPLEX, AND FUNCTION.
RX PubMed=19995937; DOI=10.1083/jcb.200906117;
RA Maerki S., Olma M.H., Staubli T., Steigemann P., Gerlich D.W.,
RA Quadroni M., Sumara I., Peter M.;
RT "The Cul3-KLHL21 E3 ubiquitin ligase targets aurora B to midzone
RT microtubules in anaphase and is required for cytokinesis.";
RL J. Cell Biol. 187:791-800(2009).
RN [27]
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 [28]
RP FUNCTION, SUBCELLULAR LOCATION, AND IDENTIFICATION IN A COMPLEX WITH
RP SPOP AND BRMS1.
RX PubMed=22085717; DOI=10.1016/j.bbrc.2011.10.154;
RA Kim B., Nam H.J., Pyo K.E., Jang M.J., Kim I.S., Kim D., Boo K.,
RA Lee S.H., Yoon J.B., Baek S.H., Kim J.H.;
RT "Breast cancer metastasis suppressor 1 (BRMS1) is destabilized by the
RT Cul3-SPOP E3 ubiquitin ligase complex.";
RL Biochem. Biophys. Res. Commun. 415:720-726(2011).
RN [29]
RP INTERACTION WITH KCTD7.
RX PubMed=22748208; DOI=10.1016/j.ajhg.2012.05.023;
RA Staropoli J.F., Karaa A., Lim E.T., Kirby A., Elbalalesy N.,
RA Romansky S.G., Leydiker K.B., Coppel S.H., Barone R., Xin W.,
RA MacDonald M.E., Abdenur J.E., Daly M.J., Sims K.B., Cotman S.L.;
RT "A homozygous mutation in KCTD7 links neuronal ceroid lipofuscinosis
RT to the ubiquitin-proteasome system.";
RL Am. J. Hum. Genet. 91:202-208(2012).
RN [30]
RP IDENTIFICATION IN THE BCR(KLHL25) COMPLEX, AND FUNCTION.
RX PubMed=22578813; DOI=10.1016/j.molcel.2012.04.004;
RA Yanagiya A., Suyama E., Adachi H., Svitkin Y.V., Aza-Blanc P.,
RA Imataka H., Mikami S., Martineau Y., Ronai Z.A., Sonenberg N.;
RT "Translational homeostasis via the mRNA cap-binding protein, eIF4E.";
RL Mol. Cell 46:847-858(2012).
RN [31]
RP IDENTIFICATION IN THE BCR(KLHL12) COMPLEX, AND FUNCTION.
RX PubMed=22358839; DOI=10.1038/nature10822;
RA Jin L., Pahuja K.B., Wickliffe K.E., Gorur A., Baumgartel C.,
RA Schekman R., Rape M.;
RT "Ubiquitin-dependent regulation of COPII coat size and function.";
RL Nature 482:495-500(2012).
RN [32]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
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).
RN [33]
RP FUNCTION, AND INTERACTION WITH KLHL3.
RX PubMed=23387299; DOI=10.1042/BJ20121903;
RA Ohta A., Schumacher F.R., Mehellou Y., Johnson C., Knebel A.,
RA Macartney T.J., Wood N.T., Alessi D.R., Kurz T.;
RT "The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension
RT syndrome interacts with and ubiquitylates WNK isoforms: disease-
RT causing mutations in KLHL3 and WNK4 disrupt interaction.";
RL Biochem. J. 451:111-122(2013).
RN [34]
RP FUNCTION, AND IDENTIFICATION IN THE BCR(KLHL3) COMPLEX.
RX PubMed=23453970; DOI=10.1016/j.celrep.2013.02.024;
RA Wakabayashi M., Mori T., Isobe K., Sohara E., Susa K., Araki Y.,
RA Chiga M., Kikuchi E., Nomura N., Mori Y., Matsuo H., Murata T.,
RA Nomura S., Asano T., Kawaguchi H., Nonoyama S., Rai T., Sasaki S.,
RA Uchida S.;
RT "Impaired KLHL3-mediated ubiquitination of WNK4 causes human
RT hypertension.";
RL Cell Rep. 3:858-868(2013).
RN [35]
RP IDENTIFICATION IN THE BCR(KLHL22) COMPLEX, AND FUNCTION.
RX PubMed=23455478; DOI=10.1038/ncb2695;
RA Beck J., Maerki S., Posch M., Metzger T., Persaud A., Scheel H.,
RA Hofmann K., Rotin D., Pedrioli P., Swedlow J.R., Peter M., Sumara I.;
RT "Ubiquitylation-dependent localization of PLK1 in mitosis.";
RL Nat. Cell Biol. 15:430-439(2013).
RN [36]
RP FUNCTION, AND IDENTIFICATION IN THE BCR(KLHL3) COMPLEX.
RX PubMed=23576762; DOI=10.1073/pnas.1304592110;
RA Shibata S., Zhang J., Puthumana J., Stone K.L., Lifton R.P.;
RT "Kelch-like 3 and Cullin 3 regulate electrolyte homeostasis via
RT ubiquitination and degradation of WNK4.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:7838-7843(2013).
RN [37]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 20-381 IN COMPLEX WITH SPOP,
RP FUNCTION, IDENTIFICATION IN UBIQUITIN LIGASE COMPLEXES WITH SPOP AND
RP SPOPL, AND SUBUNIT.
RX PubMed=22632832; DOI=10.1016/j.str.2012.04.009;
RA Errington W.J., Khan M.Q., Bueler S.A., Rubinstein J.L.,
RA Chakrabartty A., Prive G.G.;
RT "Adaptor protein self-assembly drives the control of a cullin-RING
RT ubiquitin ligase.";
RL Structure 20:1141-1153(2012).
RN [38]
RP X-RAY CRYSTALLOGRAPHY (3.51 ANGSTROMS) OF 20-381 IN COMPLEX WITH
RP KLHL3.
RX PubMed=23573258; DOI=10.1371/journal.pone.0060445;
RA Ji A.X., Prive G.G.;
RT "Crystal structure of KLHL3 in complex with Cullin3.";
RL PLoS ONE 8:E60445-E60445(2013).
RN [39]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 1-388 IN COMPLEX WITH KLHL11,
RP AND INTERACTION WITH KLHL11.
RX PubMed=23349464; DOI=10.1074/jbc.M112.437996;
RA Canning P., Cooper C.D., Krojer T., Murray J.W., Pike A.C.,
RA Chaikuad A., Keates T., Thangaratnarajah C., Hojzan V., Marsden B.D.,
RA Gileadi O., Knapp S., von Delft F., Bullock A.N.;
RT "Structural basis for Cul3 assembly with the BTB-Kelch family of E3
RT ubiquitin ligases.";
RL J. Biol. Chem. 288:7803-7814(2013).
RN [40]
RP VARIANTS PHA2E GLY-413 AND ARG-459.
RX PubMed=22266938; DOI=10.1038/nature10814;
RA Boyden L.M., Choi M., Choate K.A., Nelson-Williams C.J., Farhi A.,
RA Toka H.R., Tikhonova I.R., Bjornson R., Mane S.M., Colussi G.,
RA Lebel M., Gordon R.D., Semmekrot B.A., Poujol A., Valimaki M.J.,
RA De Ferrari M.E., Sanjad S.A., Gutkin M., Karet F.E., Tucci J.R.,
RA Stockigt J.R., Keppler-Noreuil K.M., Porter C.C., Anand S.K.,
RA Whiteford M.L., Davis I.D., Dewar S.B., Bettinelli A., Fadrowski J.J.,
RA Belsha C.W., Hunley T.E., Nelson R.D., Trachtman H., Cole T.R.,
RA Pinsk M., Bockenhauer D., Shenoy M., Vaidyanathan P., Foreman J.W.,
RA Rasoulpour M., Thameem F., Al-Shahrouri H.Z., Radhakrishnan J.,
RA Gharavi A.G., Goilav B., Lifton R.P.;
RT "Mutations in kelch-like 3 and cullin 3 cause hypertension and
RT electrolyte abnormalities.";
RL Nature 482:98-102(2012).
CC -!- FUNCTION: Core component of multiple cullin-RING-based BCR (BTB-
CC CUL3-RBX1) E3 ubiquitin-protein ligase complexes which mediate the
CC ubiquitination and subsequent proteasomal degradation of target
CC proteins. As a scaffold protein may contribute to catalysis
CC through positioning of the substrate and the ubiquitin-conjugating
CC enzyme. The E3 ubiquitin-protein ligase activity of the complex is
CC dependent on the neddylation of the cullin subunit and is
CC inhibited by the association of the deneddylated cullin subunit
CC with TIP120A/CAND1 (By similarity). The functional specificity of
CC the BCR complex depends on the BTB domain-containing protein as
CC the substrate recognition component. BCR(KLHL42) is involved in
CC ubiquitination of KATNA1. BCR(SPOP) is involved in ubiquitination
CC of BMI1/PCGF4, BRMS1, H2AFY and DAXX, GLI2 and GLI3. Can also form
CC a cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein
CC ligase complex containing homodimeric SPOPL or the heterodimer
CC formed by SPOP and SPOPL; these complexes have lower ubiquitin
CC ligase activity. BCR(KLHL9-KLHL13) controls the dynamic behavior
CC of AURKB on mitotic chromosomes and thereby coordinates faithful
CC mitotic progression and completion of cytokinesis. BCR(KLHL12) is
CC involved in ER-Golgi transport by regulating the size of COPII
CC coats, thereby playing a key role in collagen export, which is
CC required for embryonic stem (ES) cells division: BCR(KLHL12) acts
CC by mediating monoubiquitination of SEC31 (SEC31A or SEC31B).
CC BCR(KLHL3) acts as a regulator of ion transport in the distal
CC nephron; by mediating ubiquitination of WNK4. The BCR(KLHL21) E3
CC ubiquitin ligase complex regulates localization of the chromosomal
CC passenger complex (CPC) from chromosomes to the spindle midzone in
CC anaphase and mediates the ubiquitination of AURKB. The BCR(KLHL22)
CC ubiquitin ligase complex mediates monoubiquitination of PLK1,
CC leading to PLK1 dissociation from phosphoreceptor proteins and
CC subsequent removal from kinetochores, allowing silencing of the
CC spindle assembly checkpoint (SAC) and chromosome segregation. The
CC BCR(KLHL25) ubiquitin ligase complex is involved in translational
CC homeostasis by mediating ubiquitination and subsequent degradation
CC of hypophosphorylated EIF4EBP1 (4E-BP1). Involved in
CC ubiquitination of cyclin E and of cyclin D1 (in vitro) thus
CC involved in regulation of G1/S transition. Involved in the
CC ubiquitination of KEAP1, ENC1 and KLHL41. In concert with ATF2 and
CC RBX1, promotes degradation of KAT5 thereby attenuating its ability
CC to acetylate and activate ATM.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Forms neddylation-dependent homodimers. Component of
CC multiple BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes
CC formed of CUL3, RBX1 and a variable BTB domain-containing protein
CC acting as both, adapter to cullin and substrate recognition
CC subunit. The BCR complex may be active as a heterodimeric complex,
CC in which NEDD8, covalently attached to one CUL3 molecule, binds to
CC the C-terminus of a second CUL3 molecule. Interacts with RBX1,
CC RNF7, CYCE and TIP120A/CAND1. Part of the BCR(SPOP) containing
CC SPOP, and of BCR containing homodimeric SPOPL or the heterodimer
CC formed by SPOP and SPOPL. Part of the probable BCR(KLHL9-KLHL13)
CC complex with BTB domain proteins KLHL9 and KLHL13. Part of the
CC BCR(KLHL41) complex containing KLHL41. Component of the
CC BCR(KLHL12) E3 ubiquitin ligase complex, at least composed of CUL3
CC and KLHL12 and RBX1. Component of the BCR(KLHL3) E3 ubiquitin
CC ligase complex, at least composed of CUL3 and KLHL3 and RBX1
CC (Probable). Part of the BCR(ENC1) complex containing ENC1. Part of
CC a complex consisting of BMI1/PCGF4, CUL3 and SPOP. Part of a
CC complex consisting of BRMS1, CUL3 and SPOP. Component of the
CC BCR(KLHL21) E3 ubiquitin ligase complex, at least composed of
CC CUL3, KLHL21 and RBX1. Component of the BCR(KLHL22) E3 ubiquitin
CC ligase complex, at least composed of CUL3, KLHL22 and RBX1.
CC Component of the BCR(KLHL25) E3 ubiquitin ligase complex, at least
CC composed of CUL3, KLHL25 and RBX1. Part of a complex consisting of
CC H2AFY, CUL3 and SPOP. Component of the BCR(KLHL42) E3 ubiquitin
CC ligase complex, at least composed of CUL3 and KLHL42. Interacts
CC with KLHL42 (via the BTB domain). Interacts with KATNA1; the
CC interaction is enhanced by KLHL42. Interacts with KCTD5, KLHL9,
CC KLHL11, KLHL13, GAN, ZBTB16, KLHL3, KLHL15, KLHL20, KLHL36,
CC GMCL1P1, BTBD1. Part of a complex that contains CUL3, RBX1 and
CC GAN. Interacts (via BTB domain) with KLHL17; the interaction
CC regulates surface GRIK2 expression. Interacts with KCTD7. Part of
CC the BCR(GAN) complex containing GAN. Part of the BCR(KEAP1)
CC complex containing KEAP1. Interacts with KLHL10 (By similarity).
CC Interacts with KAT5 and ATF2.
CC -!- INTERACTION:
CC Q86VP6:CAND1; NbExp=2; IntAct=EBI-456129, EBI-456077;
CC Q14790:CASP8; NbExp=6; IntAct=EBI-456129, EBI-78060;
CC P08238:HSP90AB1; NbExp=2; IntAct=EBI-456129, EBI-352572;
CC Q9Y2M5:KLHL20; NbExp=2; IntAct=EBI-456129, EBI-7904035;
CC O43791:SPOP; NbExp=2; IntAct=EBI-456129, EBI-743549;
CC P50591:TNFSF10; NbExp=2; IntAct=EBI-456129, EBI-495373;
CC -!- SUBCELLULAR LOCATION: Nucleus. Golgi apparatus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=Cul-3 Long;
CC IsoId=Q13618-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q13618-2; Sequence=VSP_008824;
CC Name=3; Synonyms=Cul-3 Short;
CC IsoId=Q13618-3; Sequence=VSP_008825;
CC -!- TISSUE SPECIFICITY: Widely expressed.
CC -!- PTM: Neddylated. Attachment of NEDD8 is required for the E3
CC ubiquitin-protein ligase activity of the BCR complex. Deneddylated
CC via its interaction with the COP9 signalosome (CSN) complex.
CC -!- DISEASE: Pseudohypoaldosteronism 2E (PHA2E) [MIM:614496]: An
CC autosomal dominant disorder characterized by severe hypertension,
CC hyperkalemia, hyperchloremia, hyperchloremic metabolic acidosis,
CC and correction of physiologic abnormalities by thiazide diuretics.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the cullin family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAC28621.1; Type=Frameshift; Positions=452;
CC Sequence=AAC36682.1; Type=Frameshift; Positions=159, 179;
CC Sequence=BAA31592.2; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AF064087; AAC36304.1; -; mRNA.
DR EMBL; AB014517; BAA31592.2; ALT_INIT; mRNA.
DR EMBL; AF062537; AAC36682.1; ALT_FRAME; mRNA.
DR EMBL; AY337761; AAQ01660.1; -; mRNA.
DR EMBL; AK291151; BAF83840.1; -; mRNA.
DR EMBL; AC073052; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC092679; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471063; EAW70828.1; -; Genomic_DNA.
DR EMBL; BC031844; AAH31844.1; -; mRNA.
DR EMBL; BC039598; AAH39598.1; -; mRNA.
DR EMBL; BC092409; AAH92409.1; -; mRNA.
DR EMBL; U58089; AAC50546.1; -; mRNA.
DR EMBL; AF052147; AAC28621.1; ALT_FRAME; mRNA.
DR RefSeq; NP_001244126.1; NM_001257197.1.
DR RefSeq; NP_001244127.1; NM_001257198.1.
DR RefSeq; NP_003581.1; NM_003590.4.
DR UniGene; Hs.372286; -.
DR PDB; 4AP2; X-ray; 2.80 A; B=1-388.
DR PDB; 4APF; X-ray; 3.10 A; B=23-388.
DR PDB; 4EOZ; X-ray; 2.40 A; B/D=20-381.
DR PDB; 4HXI; X-ray; 3.51 A; B=20-381.
DR PDBsum; 4AP2; -.
DR PDBsum; 4APF; -.
DR PDBsum; 4EOZ; -.
DR PDBsum; 4HXI; -.
DR ProteinModelPortal; Q13618; -.
DR SMR; Q13618; 17-768.
DR DIP; DIP-31611N; -.
DR IntAct; Q13618; 38.
DR MINT; MINT-3028280; -.
DR STRING; 9606.ENSP00000264414; -.
DR PhosphoSite; Q13618; -.
DR DMDM; 12643396; -.
DR PaxDb; Q13618; -.
DR PRIDE; Q13618; -.
DR Ensembl; ENST00000264414; ENSP00000264414; ENSG00000036257.
DR Ensembl; ENST00000344951; ENSP00000343601; ENSG00000036257.
DR Ensembl; ENST00000409096; ENSP00000387200; ENSG00000036257.
DR Ensembl; ENST00000409777; ENSP00000386525; ENSG00000036257.
DR GeneID; 8452; -.
DR KEGG; hsa:8452; -.
DR UCSC; uc002vny.3; human.
DR CTD; 8452; -.
DR GeneCards; GC02M225298; -.
DR HGNC; HGNC:2553; CUL3.
DR HPA; CAB002678; -.
DR MIM; 603136; gene.
DR MIM; 614496; phenotype.
DR neXtProt; NX_Q13618; -.
DR Orphanet; 300530; Pseudohypoaldosteronism type 2E.
DR PharmGKB; PA27049; -.
DR eggNOG; COG5647; -.
DR HOVERGEN; HBG003619; -.
DR InParanoid; Q13618; -.
DR KO; K03869; -.
DR OMA; IHTKNAS; -.
DR OrthoDB; EOG7C5M7H; -.
DR PhylomeDB; Q13618; -.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; Q13618; -.
DR UniPathway; UPA00143; -.
DR ChiTaRS; CUL3; human.
DR GeneWiki; CUL3; -.
DR GenomeRNAi; 8452; -.
DR NextBio; 31630; -.
DR PRO; PR:Q13618; -.
DR ArrayExpress; Q13618; -.
DR Bgee; Q13618; -.
DR CleanEx; HS_CUL3; -.
DR Genevestigator; Q13618; -.
DR GO; GO:0031463; C:Cul3-RING ubiquitin ligase complex; IDA:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005827; C:polar microtubule; IDA:UniProtKB.
DR GO; GO:0031208; F:POZ domain binding; IDA:UniProtKB.
DR GO; GO:0007050; P:cell cycle arrest; TAS:ProtInc.
DR GO; GO:0016477; P:cell migration; IMP:UniProtKB.
DR GO; GO:0048208; P:COPII vesicle coating; IMP:UniProtKB.
DR GO; GO:0008054; P:cyclin catabolic process; IDA:MGI.
DR GO; GO:0000910; P:cytokinesis; IMP:UniProtKB.
DR GO; GO:0040016; P:embryonic cleavage; ISS:UniProtKB.
DR GO; GO:0000082; P:G1/S transition of mitotic cell cycle; TAS:ProtInc.
DR GO; GO:0007369; P:gastrulation; IEA:Ensembl.
DR GO; GO:0007229; P:integrin-mediated signaling pathway; ISS:UniProtKB.
DR GO; GO:0097193; P:intrinsic apoptotic signaling pathway; TAS:ProtInc.
DR GO; GO:0000090; P:mitotic anaphase; IMP:UniProtKB.
DR GO; GO:0035024; P:negative regulation of Rho protein signal transduction; IMP:UniProtKB.
DR GO; GO:0008284; P:positive regulation of cell proliferation; TAS:ProtInc.
DR GO; GO:0032467; P:positive regulation of cytokinesis; IMP:UniProtKB.
DR GO; GO:0006513; P:protein monoubiquitination; IDA:UniProtKB.
DR GO; GO:0000209; P:protein polyubiquitination; IDA:UniProtKB.
DR GO; GO:0017145; P:stem cell division; ISS:UniProtKB.
DR GO; GO:0043149; P:stress fiber assembly; IMP:UniProtKB.
DR GO; GO:0001831; P:trophectodermal cellular morphogenesis; IEA:Ensembl.
DR GO; GO:0016055; P:Wnt receptor signaling pathway; IEA:Ensembl.
DR Gene3D; 1.10.10.10; -; 2.
DR InterPro; IPR016157; Cullin_CS.
DR InterPro; IPR016158; Cullin_homology.
DR InterPro; IPR001373; Cullin_N.
DR InterPro; IPR019559; Cullin_neddylation_domain.
DR InterPro; IPR016159; Cullin_repeat-like_dom.
DR InterPro; IPR011991; WHTH_DNA-bd_dom.
DR Pfam; PF00888; Cullin; 1.
DR Pfam; PF10557; Cullin_Nedd8; 1.
DR SMART; SM00182; CULLIN; 1.
DR SMART; SM00884; Cullin_Nedd8; 1.
DR SUPFAM; SSF74788; SSF74788; 1.
DR SUPFAM; SSF75632; SSF75632; 1.
DR PROSITE; PS01256; CULLIN_1; 1.
DR PROSITE; PS50069; CULLIN_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Disease mutation; ER-Golgi transport; Golgi apparatus;
KW Isopeptide bond; Nucleus; Polymorphism; Reference proteome; Transport;
KW Ubl conjugation; Ubl conjugation pathway.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 768 Cullin-3.
FT /FTId=PRO_0000119793.
FT MOD_RES 2 2 N-acetylserine.
FT CROSSLNK 712 712 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in NEDD8) (By
FT similarity).
FT VAR_SEQ 1 24 Missing (in isoform 2).
FT /FTId=VSP_008824.
FT VAR_SEQ 23 88 Missing (in isoform 3).
FT /FTId=VSP_008825.
FT VARIANT 13 13 D -> H (in dbSNP:rs2969802).
FT /FTId=VAR_017194.
FT VARIANT 184 184 R -> S (in dbSNP:rs17480168).
FT /FTId=VAR_048839.
FT VARIANT 413 413 D -> G (in PHA2E).
FT /FTId=VAR_067532.
FT VARIANT 459 459 K -> R (in PHA2E).
FT /FTId=VAR_067533.
FT VARIANT 567 567 V -> I (in dbSNP:rs3738952).
FT /FTId=VAR_017195.
FT CONFLICT 13 13 D -> G (in Ref. 3; AAC36682).
FT CONFLICT 397 397 K -> T (in Ref. 4; AAQ01660).
FT CONFLICT 481 481 N -> T (in Ref. 4; AAQ01660).
FT CONFLICT 609 609 E -> G (in Ref. 8; AAH31844).
FT CONFLICT 666 666 T -> I (in Ref. 4; AAQ01660).
FT HELIX 26 45
FT HELIX 49 51
FT HELIX 54 66
FT HELIX 70 87
FT HELIX 89 94
FT TURN 95 98
FT HELIX 101 122
FT HELIX 124 129
FT HELIX 132 134
FT HELIX 139 150
FT TURN 151 153
FT HELIX 155 173
FT HELIX 180 192
FT STRAND 195 198
FT HELIX 199 204
FT HELIX 206 227
FT HELIX 230 251
FT HELIX 254 256
FT HELIX 257 268
FT TURN 269 272
FT HELIX 273 277
FT TURN 280 282
FT HELIX 284 287
FT TURN 288 291
FT HELIX 293 303
FT HELIX 309 323
FT HELIX 339 358
FT HELIX 364 380
SQ SEQUENCE 768 AA; 88930 MW; A1A02022480BF099 CRC64;
MSNLSKGTGS RKDTKMRIRA FPMTMDEKYV NSIWDLLKNA IQEIQRKNNS GLSFEELYRN
AYTMVLHKHG EKLYTGLREV VTEHLINKVR EDVLNSLNNN FLQTLNQAWN DHQTAMVMIR
DILMYMDRVY VQQNNVENVY NLGLIIFRDQ VVRYGCIRDH LRQTLLDMIA RERKGEVVDR
GAIRNACQML MILGLEGRSV YEEDFEAPFL EMSAEFFQME SQKFLAENSA SVYIKKVEAR
INEEIERVMH CLDKSTEEPI VKVVERELIS KHMKTIVEME NSGLVHMLKN GKTEDLGCMY
KLFSRVPNGL KTMCECMSSY LREQGKALVS EEGEGKNPVD YIQGLLDLKS RFDRFLLESF
NNDRLFKQTI AGDFEYFLNL NSRSPEYLSL FIDDKLKKGV KGLTEQEVET ILDKAMVLFR
FMQEKDVFER YYKQHLARRL LTNKSVSDDS EKNMISKLKT ECGCQFTSKL EGMFRDMSIS
NTTMDEFRQH LQATGVSLGG VDLTVRVLTT GYWPTQSATP KCNIPPAPRH AFEIFRRFYL
AKHSGRQLTL QHHMGSADLN ATFYGPVKKE DGSEVGVGGA QVTGSNTRKH ILQVSTFQMT
ILMLFNNREK YTFEEIQQET DIPERELVRA LQSLACGKPT QRVLTKEPKS KEIENGHIFT
VNDQFTSKLH RVKIQTVAAK QGESDPERKE TRQKVDDDRK HEIEAAIVRI MKSRKKMQHN
VLVAEVTQQL KARFLPSPVV IKKRIEGLIE REYLARTPED RKVYTYVA
//
MIM
603136
*RECORD*
*FIELD* NO
603136
*FIELD* TI
*603136 CULLIN 3; CUL3
*FIELD* TX
DESCRIPTION
CUL3 is a component of a ubiquitin E3 ligase that is essential for
read moremitotic division (Sumara et al., 2007).
CLONING
Kipreos et al. (1996) identified a conserved gene family, designated
cullins (see CUL1; 603134), with at least 5 members in nematodes, 6 in
humans, and 3 in S. cerevisiae. Human CUL3 is an ortholog of nematode
cul3. Michel and Xiong (1998) identified human CUL3 cDNAs and reported
that the predicted protein is 768 amino acids long.
Ishikawa et al. (1998) isolated a CUL3 cDNA, KIAA0617, as 1 of 100 brain
cDNAs encoding large proteins. Using RT-PCR, they found that CUL3 is
expressed in several tissues.
Du et al. (1998) identified CUL3 as a gene whose expression in human
fibroblasts was induced by phorbol 12-myristate 13-acetate (PMA) and
suppressed by salicylate. They reported that the sequences of the human
and C. elegans cul3 proteins share 46% identity. Northern blot analysis
revealed that CUL3 is expressed as major 2.8- and minor 4.3-kb
transcripts in various human tissues, with the highest levels in
skeletal muscle and heart.
GENE FUNCTION
Sumara et al. (2007) found that KLHL9 (611201), KLHL13 (300655), and
CUL3 interacted directly in a 370-kD protein complex in HeLa cell
lysates. The CUL3/KLHL9/KLHL13 complex was the minimum unit required for
correct chromosome alignment in metaphase, proper midzone and midbody
formation, and completion of cytokinesis. CUL3/KLHL9/KLHL13 acted as an
E3 ligase and regulated dynamic localization of the chromosomal
passenger protein Aurora B (AURKB; 604970) on mitotic chromosomes and
accumulation of Aurora B on the central spindle after anaphase onset.
Aurora B directly bound the substrate-recognition domains of KLHL9 and
KLHL13 in vitro and coimmunoprecipitated with the CUL3/KLHL9/KLHL13
complex during mitosis. Moreover, Aurora B was ubiquitylated in a
CUL3-dependent manner in vivo and by reconstituted CUL3/KLHL9/KLHL13 in
vitro. Sumara et al. (2007) concluded that CUL3/KLHL9/KLHL13 is an E3
ligase that controls the dynamic behavior of Aurora B on mitotic
chromosomes and thereby coordinates faithful mitotic progression and
completion of cytokinesis.
Rondou et al. (2008) showed that interaction between KLHL12 (614522) and
the CUL3 ubiquitin ligase complex directed ubiquitination of dopamine
receptor D4 (DRD4; 126452). KLHL12 interacted directly with CUL3 and
with the polymorphic intracellular loop-3 of D4. Knockdown of KLHL12 in
KLHL12-overexpressing HEK293 cells abolished association of D4 with
CUL3, and knockdown of CUL3 decreased ubiquitination of D4.
By immunoprecipitation analysis of HeLa cells and HCT116 human colon
carcinoma cells expressing epitope-tagged proteins, Kigoshi et al.
(2011) showed that KLHL7 (611119) interacted with CUL3 and ROC1 (RBX1;
603814). Mutation analysis showed that the BTB and BACK domains of KLHL7
mediated interaction with CUL3.
Jin et al. (2012) found that depletion of either Klhl12 or Cul3 in mouse
embryonic stem cells resulted in cell compaction and delayed
proliferation. Depletion of Cul3 in mouse fibroblasts had a much weaker
effect. Overexpression and depletion studies showed that interaction of
Klhl12 with Cul3 was required for monoubiquitination of the coat protein
complex II (COPII) component Sec31 (see 610257). Overexpression of
Klhl12 resulted in expansion of the diameter of Sec31-containing COPII
vesicles, and this expansion was required for transport and secretion of
large cargo proteins, such as procollagens (see 120150). A Sec31-binding
mutant of Klhl12 neither colocalized with Sec31 nor induced formation of
large vesicles. Disruption of KLHL12-CUL3 function in human HT1080
fibrosarcoma cells impaired COPII vesicle expansion and collagen export,
but it had no effect on export of smaller cargo by small COPII vesicles.
Jin et al. (2012) concluded that KLHL12-CUL3 monoubiquitination of SEC31
is required for COPII vesicle expansion to accommodate large or bulky
cargo molecules.
Mathew et al. (2012) reported that PLZF is prominently associated with
CUL3 in natural killer T cell thymocytes. PLZF transports CUL3 to the
nucleus, where the 2 proteins are associated within a chromatin
modifying complex. Furthermore, PLZF expression results in selective
ubiquitination changes of several components of this complex. CUL3 was
also found associated with the BTB-ZF transcription factor BCL6
(109565), which directs the germinal center B cell and follicular
T-helper cell programs. Conditional CUL3 deletion in mice demonstrated
an essential role for CUL3 in the development of PLZF- and
BCL6-dependent lineages. Mathew et al. (2012) concluded that distinct
lineage-specific BTB-ZF transcription factors recruit CUL3 to alter the
ubiquitination pattern of their associated chromatin-modifying complex.
They proposed that this function is essential to direct the
differentiation of several T- and B-cell effector programs, and may also
be involved in the oncogenic role of PLZF and BCL6 in leukemias and
lymphomas.
MAPPING
By analysis of a radiation hybrid panel, Ishikawa et al. (1998) mapped
the CUL3 gene to human chromosome 2.
Hartz (2012) mapped the CUL3 gene to chromosome 2q36.2 based on an
alignment of the CUL3 sequence (GenBank GENBANK AF062537) with the
genomic sequence (GRCh37).
MOLECULAR GENETICS
Boyden et al. (2012) identified mutations in CUL3 segregating in de novo
or autosomal dominant forms of pseudohypoaldosteronism type II (PHA2E;
614496). Seventeen of 52 PHA2 kindreds had mutations in CUL3; all were
heterozygous. Eight of the 17 were documented to be de novo, providing
overwhelming evidence that these mutations are disease-causing. CUL3
mutations all clustered in sites implicated in splicing of exon 9,
including the intron 8 splice acceptor (n = 4), the intron 9 splice
donor (n = 5), the putative intron 8 splice branch site (n = 5), and a
putative splice enhancer in exon 9 (n = 3, within a TTGGA(T/A)) splice
enhancer consensus sequence.
*FIELD* AV
.0001
PSEUDOHYPOALDOSTERONISM, TYPE IIE
CUL3, IVS8, A-G, -26
In 4 families, 3 with de novo occurrence of pseudohypoaldosteronism,
type IIE (PHA2E; 614496), Boyden et al. (2012) identified an A-to-G
transition at the -26 position of the intron 8 splice acceptor site in
the CUL3 gene.
.0002
PSEUDOHYPOALDOSTERONISM, TYPE IIE
CUL3, IVS8, T-G, -28
In a family segregating autosomal dominant pseudohypoaldosteronism type
IIE (PHA2E; 614496), Boyden et al. (2012) identified an T-to-G
transversion at the -28 position of the intron 8 splice branch point in
the CUL3 gene.
.0003
PSEUDOHYPOALDOSTERONISM, TYPE IIE
CUL3, IVS8, T-G, -12
In a patient with pseudohypoaldosteronism type IIE (PHA2E; 614496),
Boyden et al. (2012) identified an T-to-G transversion in the CUL3 gene,
at the -12 position of the intron 8 splice acceptor site, within the
polypyrimidine tract.
.0004
PSEUDOHYPOALDOSTERONISM, TYPE IIE
CUL3, IVS8, T-A, -5
In a de novo case of pseudohypoaldosteronism type IIE (PHA2E; 614496),
Boyden et al. (2012) identified an T-to-A transversion in the CUL3 gene,
at the -5 position of the intron 8 splice acceptor site, within the
polypyrimidine tract.
.0005
PSEUDOHYPOALDOSTERONISM, TYPE IIE
CUL3, IVS8, C-T, -3
In a de novo case of pseudohypoaldosteronism type IIE (PHA2E; 614496),
Boyden et al. (2012) identified a C-to-T transition at the -3 position
of the intron 8 splice acceptor site of the CUL3 gene.
.0006
PSEUDOHYPOALDOSTERONISM, TYPE IIE
CUL3, IVS8, G-A, -1
In 3 affected members of a 2-generation family with
pseudohypoaldosteronism type IIE (PHA2E; 614496), Boyden et al. (2012)
identified a G-to-A transition in the CUL3 gene, at the -1 position of
the intron 8 splice acceptor site.
.0007
PSEUDOHYPOALDOSTERONISM, TYPE IIE
CUL3, ASP413GLY
In 2 families with undetermined pseudohypoaldosteronism type IIE (PHA2E;
614496), Boyden et al. (2012) identified an A-to-G transition resulting
in an asp-to-gly substitution at codon 413 (D413G) within exon 9 of the
CUL3 gene that resulted in an ES enhancer.
*FIELD* RF
1. Boyden, L. M.; Choi, M.; Choate, K. A.; Nelson-Williams, C. J.;
Farhi, A.; Toka, H. R.; Tikhonova, I. R.; Bjornson, R.; Mane, S. M.;
Colussi, G.; Lebel, M.; Gordon, R. D.; and 34 others: Mutations
in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature 482:
98-102, 2012.
2. Du, M.; Sansores-Garcia, L.; Zu, Z.; Wu, K. K.: Cloning and expression
analysis of a novel salicylate suppressible gene, Hs-CUL-3, a member
of cullin/Cdc53 family. J. Biol. Chem. 273: 24289-24292, 1998.
3. Hartz, P. A.: Personal Communication. Baltimore, Md. 3/14/2012.
4. Ishikawa, K.; Nagase, T.; Suyama, M.; Miyajima, N.; Tanaka, A.;
Kotani, H.; Nomura, N.; Ohara, O.: Prediction of the coding sequences
of unidentified human genes. X. The complete sequences of 100 new
cDNA clones from brain which can code for large proteins in vitro. DNA
Res. 5: 169-176, 1998.
5. Jin, L.; Pahuja, K. B.; Wickliffe, K. E.; Gorur, A.; Baumgartel,
C.; Schekman, R.; Rape, M.: Ubiquitin-dependent regulation of COPII
coat size and function. Nature 482: 495-500, 2012.
6. Kigoshi, Y.; Tsuruta, F.; Chiba, T.: Ubiquitin ligase activity
of Cul3-KLHL7 protein is attenuated by autosomal dominant retinitis
pigmentosa causative mutation. J. Biol. Chem. 286: 33613-33621,
2011.
7. Kipreos, E. T.; Lander, L. E.; Wing, J. P.; He, W. W.; Hedgecock,
E. M.: cul-1 is required for cell cycle exit in C. elegans and identifies
a novel gene family. Cell 85: 829-839, 1996.
8. Mathew, R.; Seiler, M. P.; Scanlon, S. T.; Mao, A.; Constantinides,
M. G.; Bertozzi-Villa, C.; Singer, J. D.; Bendelac, A.: BTB-ZF factors
recruit the E3 ligase cullin 3 to regulate lymphoid effector programs. Nature 491:
618-621, 2012.
9. Michel, J. J.; Xiong, Y.: Human CUL-1, but not other cullin family
members, selectively interacts with SKP1 to form a complex with SKP2
and cyclin A. Cell Growth Differ. 9: 435-449, 1998.
10. Rondou, P.; Haegeman, G.; Vanhoenacker, P.; Van Craenenbroeck,
K.: BTB protein KLHL12 targets the dopamine D4 receptor for ubiquitination
by a Cul3-based E3 ligase. J. Biol. Chem. 283: 11083-11096, 2008.
11. Sumara, I.; Quadroni, M.; Frei, C.; Olma, M. H.; Sumara, G.; Ricci,
R.; Peter, M.: A Cul3-based E3 ligase removes Aurora B from mitotic
chromosomes, regulating mitotic progression and completion of cytokinesis
in human cells. Dev. Cell 12: 887-900, 2007.
*FIELD* CN
Ada Hamosh - updated: 12/13/2012
Patricia A. Hartz - updated: 3/14/2012
Patricia A. Hartz - updated: 3/8/2012
Ada Hamosh - updated: 2/22/2012
Patricia A. Hartz - updated: 6/26/2007
*FIELD* CD
Rebekah S. Rasooly: 10/13/1998
*FIELD* ED
alopez: 12/21/2012
terry: 12/13/2012
mgross: 5/23/2012
terry: 3/14/2012
mgross: 3/8/2012
terry: 3/8/2012
alopez: 2/27/2012
terry: 2/22/2012
mgross: 7/12/2007
terry: 6/26/2007
alopez: 10/30/1998
dkim: 10/28/1998
alopez: 10/13/1998
*RECORD*
*FIELD* NO
603136
*FIELD* TI
*603136 CULLIN 3; CUL3
*FIELD* TX
DESCRIPTION
CUL3 is a component of a ubiquitin E3 ligase that is essential for
read moremitotic division (Sumara et al., 2007).
CLONING
Kipreos et al. (1996) identified a conserved gene family, designated
cullins (see CUL1; 603134), with at least 5 members in nematodes, 6 in
humans, and 3 in S. cerevisiae. Human CUL3 is an ortholog of nematode
cul3. Michel and Xiong (1998) identified human CUL3 cDNAs and reported
that the predicted protein is 768 amino acids long.
Ishikawa et al. (1998) isolated a CUL3 cDNA, KIAA0617, as 1 of 100 brain
cDNAs encoding large proteins. Using RT-PCR, they found that CUL3 is
expressed in several tissues.
Du et al. (1998) identified CUL3 as a gene whose expression in human
fibroblasts was induced by phorbol 12-myristate 13-acetate (PMA) and
suppressed by salicylate. They reported that the sequences of the human
and C. elegans cul3 proteins share 46% identity. Northern blot analysis
revealed that CUL3 is expressed as major 2.8- and minor 4.3-kb
transcripts in various human tissues, with the highest levels in
skeletal muscle and heart.
GENE FUNCTION
Sumara et al. (2007) found that KLHL9 (611201), KLHL13 (300655), and
CUL3 interacted directly in a 370-kD protein complex in HeLa cell
lysates. The CUL3/KLHL9/KLHL13 complex was the minimum unit required for
correct chromosome alignment in metaphase, proper midzone and midbody
formation, and completion of cytokinesis. CUL3/KLHL9/KLHL13 acted as an
E3 ligase and regulated dynamic localization of the chromosomal
passenger protein Aurora B (AURKB; 604970) on mitotic chromosomes and
accumulation of Aurora B on the central spindle after anaphase onset.
Aurora B directly bound the substrate-recognition domains of KLHL9 and
KLHL13 in vitro and coimmunoprecipitated with the CUL3/KLHL9/KLHL13
complex during mitosis. Moreover, Aurora B was ubiquitylated in a
CUL3-dependent manner in vivo and by reconstituted CUL3/KLHL9/KLHL13 in
vitro. Sumara et al. (2007) concluded that CUL3/KLHL9/KLHL13 is an E3
ligase that controls the dynamic behavior of Aurora B on mitotic
chromosomes and thereby coordinates faithful mitotic progression and
completion of cytokinesis.
Rondou et al. (2008) showed that interaction between KLHL12 (614522) and
the CUL3 ubiquitin ligase complex directed ubiquitination of dopamine
receptor D4 (DRD4; 126452). KLHL12 interacted directly with CUL3 and
with the polymorphic intracellular loop-3 of D4. Knockdown of KLHL12 in
KLHL12-overexpressing HEK293 cells abolished association of D4 with
CUL3, and knockdown of CUL3 decreased ubiquitination of D4.
By immunoprecipitation analysis of HeLa cells and HCT116 human colon
carcinoma cells expressing epitope-tagged proteins, Kigoshi et al.
(2011) showed that KLHL7 (611119) interacted with CUL3 and ROC1 (RBX1;
603814). Mutation analysis showed that the BTB and BACK domains of KLHL7
mediated interaction with CUL3.
Jin et al. (2012) found that depletion of either Klhl12 or Cul3 in mouse
embryonic stem cells resulted in cell compaction and delayed
proliferation. Depletion of Cul3 in mouse fibroblasts had a much weaker
effect. Overexpression and depletion studies showed that interaction of
Klhl12 with Cul3 was required for monoubiquitination of the coat protein
complex II (COPII) component Sec31 (see 610257). Overexpression of
Klhl12 resulted in expansion of the diameter of Sec31-containing COPII
vesicles, and this expansion was required for transport and secretion of
large cargo proteins, such as procollagens (see 120150). A Sec31-binding
mutant of Klhl12 neither colocalized with Sec31 nor induced formation of
large vesicles. Disruption of KLHL12-CUL3 function in human HT1080
fibrosarcoma cells impaired COPII vesicle expansion and collagen export,
but it had no effect on export of smaller cargo by small COPII vesicles.
Jin et al. (2012) concluded that KLHL12-CUL3 monoubiquitination of SEC31
is required for COPII vesicle expansion to accommodate large or bulky
cargo molecules.
Mathew et al. (2012) reported that PLZF is prominently associated with
CUL3 in natural killer T cell thymocytes. PLZF transports CUL3 to the
nucleus, where the 2 proteins are associated within a chromatin
modifying complex. Furthermore, PLZF expression results in selective
ubiquitination changes of several components of this complex. CUL3 was
also found associated with the BTB-ZF transcription factor BCL6
(109565), which directs the germinal center B cell and follicular
T-helper cell programs. Conditional CUL3 deletion in mice demonstrated
an essential role for CUL3 in the development of PLZF- and
BCL6-dependent lineages. Mathew et al. (2012) concluded that distinct
lineage-specific BTB-ZF transcription factors recruit CUL3 to alter the
ubiquitination pattern of their associated chromatin-modifying complex.
They proposed that this function is essential to direct the
differentiation of several T- and B-cell effector programs, and may also
be involved in the oncogenic role of PLZF and BCL6 in leukemias and
lymphomas.
MAPPING
By analysis of a radiation hybrid panel, Ishikawa et al. (1998) mapped
the CUL3 gene to human chromosome 2.
Hartz (2012) mapped the CUL3 gene to chromosome 2q36.2 based on an
alignment of the CUL3 sequence (GenBank GENBANK AF062537) with the
genomic sequence (GRCh37).
MOLECULAR GENETICS
Boyden et al. (2012) identified mutations in CUL3 segregating in de novo
or autosomal dominant forms of pseudohypoaldosteronism type II (PHA2E;
614496). Seventeen of 52 PHA2 kindreds had mutations in CUL3; all were
heterozygous. Eight of the 17 were documented to be de novo, providing
overwhelming evidence that these mutations are disease-causing. CUL3
mutations all clustered in sites implicated in splicing of exon 9,
including the intron 8 splice acceptor (n = 4), the intron 9 splice
donor (n = 5), the putative intron 8 splice branch site (n = 5), and a
putative splice enhancer in exon 9 (n = 3, within a TTGGA(T/A)) splice
enhancer consensus sequence.
*FIELD* AV
.0001
PSEUDOHYPOALDOSTERONISM, TYPE IIE
CUL3, IVS8, A-G, -26
In 4 families, 3 with de novo occurrence of pseudohypoaldosteronism,
type IIE (PHA2E; 614496), Boyden et al. (2012) identified an A-to-G
transition at the -26 position of the intron 8 splice acceptor site in
the CUL3 gene.
.0002
PSEUDOHYPOALDOSTERONISM, TYPE IIE
CUL3, IVS8, T-G, -28
In a family segregating autosomal dominant pseudohypoaldosteronism type
IIE (PHA2E; 614496), Boyden et al. (2012) identified an T-to-G
transversion at the -28 position of the intron 8 splice branch point in
the CUL3 gene.
.0003
PSEUDOHYPOALDOSTERONISM, TYPE IIE
CUL3, IVS8, T-G, -12
In a patient with pseudohypoaldosteronism type IIE (PHA2E; 614496),
Boyden et al. (2012) identified an T-to-G transversion in the CUL3 gene,
at the -12 position of the intron 8 splice acceptor site, within the
polypyrimidine tract.
.0004
PSEUDOHYPOALDOSTERONISM, TYPE IIE
CUL3, IVS8, T-A, -5
In a de novo case of pseudohypoaldosteronism type IIE (PHA2E; 614496),
Boyden et al. (2012) identified an T-to-A transversion in the CUL3 gene,
at the -5 position of the intron 8 splice acceptor site, within the
polypyrimidine tract.
.0005
PSEUDOHYPOALDOSTERONISM, TYPE IIE
CUL3, IVS8, C-T, -3
In a de novo case of pseudohypoaldosteronism type IIE (PHA2E; 614496),
Boyden et al. (2012) identified a C-to-T transition at the -3 position
of the intron 8 splice acceptor site of the CUL3 gene.
.0006
PSEUDOHYPOALDOSTERONISM, TYPE IIE
CUL3, IVS8, G-A, -1
In 3 affected members of a 2-generation family with
pseudohypoaldosteronism type IIE (PHA2E; 614496), Boyden et al. (2012)
identified a G-to-A transition in the CUL3 gene, at the -1 position of
the intron 8 splice acceptor site.
.0007
PSEUDOHYPOALDOSTERONISM, TYPE IIE
CUL3, ASP413GLY
In 2 families with undetermined pseudohypoaldosteronism type IIE (PHA2E;
614496), Boyden et al. (2012) identified an A-to-G transition resulting
in an asp-to-gly substitution at codon 413 (D413G) within exon 9 of the
CUL3 gene that resulted in an ES enhancer.
*FIELD* RF
1. Boyden, L. M.; Choi, M.; Choate, K. A.; Nelson-Williams, C. J.;
Farhi, A.; Toka, H. R.; Tikhonova, I. R.; Bjornson, R.; Mane, S. M.;
Colussi, G.; Lebel, M.; Gordon, R. D.; and 34 others: Mutations
in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature 482:
98-102, 2012.
2. Du, M.; Sansores-Garcia, L.; Zu, Z.; Wu, K. K.: Cloning and expression
analysis of a novel salicylate suppressible gene, Hs-CUL-3, a member
of cullin/Cdc53 family. J. Biol. Chem. 273: 24289-24292, 1998.
3. Hartz, P. A.: Personal Communication. Baltimore, Md. 3/14/2012.
4. Ishikawa, K.; Nagase, T.; Suyama, M.; Miyajima, N.; Tanaka, A.;
Kotani, H.; Nomura, N.; Ohara, O.: Prediction of the coding sequences
of unidentified human genes. X. The complete sequences of 100 new
cDNA clones from brain which can code for large proteins in vitro. DNA
Res. 5: 169-176, 1998.
5. Jin, L.; Pahuja, K. B.; Wickliffe, K. E.; Gorur, A.; Baumgartel,
C.; Schekman, R.; Rape, M.: Ubiquitin-dependent regulation of COPII
coat size and function. Nature 482: 495-500, 2012.
6. Kigoshi, Y.; Tsuruta, F.; Chiba, T.: Ubiquitin ligase activity
of Cul3-KLHL7 protein is attenuated by autosomal dominant retinitis
pigmentosa causative mutation. J. Biol. Chem. 286: 33613-33621,
2011.
7. Kipreos, E. T.; Lander, L. E.; Wing, J. P.; He, W. W.; Hedgecock,
E. M.: cul-1 is required for cell cycle exit in C. elegans and identifies
a novel gene family. Cell 85: 829-839, 1996.
8. Mathew, R.; Seiler, M. P.; Scanlon, S. T.; Mao, A.; Constantinides,
M. G.; Bertozzi-Villa, C.; Singer, J. D.; Bendelac, A.: BTB-ZF factors
recruit the E3 ligase cullin 3 to regulate lymphoid effector programs. Nature 491:
618-621, 2012.
9. Michel, J. J.; Xiong, Y.: Human CUL-1, but not other cullin family
members, selectively interacts with SKP1 to form a complex with SKP2
and cyclin A. Cell Growth Differ. 9: 435-449, 1998.
10. Rondou, P.; Haegeman, G.; Vanhoenacker, P.; Van Craenenbroeck,
K.: BTB protein KLHL12 targets the dopamine D4 receptor for ubiquitination
by a Cul3-based E3 ligase. J. Biol. Chem. 283: 11083-11096, 2008.
11. Sumara, I.; Quadroni, M.; Frei, C.; Olma, M. H.; Sumara, G.; Ricci,
R.; Peter, M.: A Cul3-based E3 ligase removes Aurora B from mitotic
chromosomes, regulating mitotic progression and completion of cytokinesis
in human cells. Dev. Cell 12: 887-900, 2007.
*FIELD* CN
Ada Hamosh - updated: 12/13/2012
Patricia A. Hartz - updated: 3/14/2012
Patricia A. Hartz - updated: 3/8/2012
Ada Hamosh - updated: 2/22/2012
Patricia A. Hartz - updated: 6/26/2007
*FIELD* CD
Rebekah S. Rasooly: 10/13/1998
*FIELD* ED
alopez: 12/21/2012
terry: 12/13/2012
mgross: 5/23/2012
terry: 3/14/2012
mgross: 3/8/2012
terry: 3/8/2012
alopez: 2/27/2012
terry: 2/22/2012
mgross: 7/12/2007
terry: 6/26/2007
alopez: 10/30/1998
dkim: 10/28/1998
alopez: 10/13/1998
MIM
614496
*RECORD*
*FIELD* NO
614496
*FIELD* TI
#614496 PSEUDOHYPOALDOSTERONISM, TYPE IIE; PHA2E
*FIELD* TX
A number sign (#) is used with this entry because
read morepseudohypoaldosteronism type IIE (PHA2E) is caused by heterozygous
mutation in the CUL3 gene (603136) on chromosome 2q36.
For a phenotypic description and a discussion of genetic heterogeneity
of pseudohypoaldosteronism type II, see PHA2A (145260).
CLINICAL FEATURES
Boyden et al. (2012) studied a cohort of 52 PHAII kindreds, including
126 affected subjects with renal hyperkalemia and otherwise normal renal
function; hypertension and acidosis were present in 71% and 82%,
respectively. They detected 21 affected individuals from 17 kindreds
with mutation in the CUL3 gene. The mean age at diagnosis or referral
was 9 +/- 6 years, mean potassium was 7.5 +/- 0.9, and mean bicarbonate
was 15.5 +/- 2.0. Hypertension was present in 94% of patients at or
before 18 years of age. The CUL3 mutation patients had by far the most
severe manifestations of PHAII compared to patients with other
mutations.
CLINICAL MANAGEMENT
Thiazide diuretics correct abnormalities in virtually all PHAII subjects
(Boyden et al., 2012).
MOLECULAR GENETICS
After identifying mutations in the KLHL3 gene (605775) in kindreds with
PHAII (see 614495), Boyden et al. (2012) considered CUL3, the presumed
functional partner of KLHL3, as a candidate. Sequencing CUL3 in 21 index
patients revealed 17 with novel heterozygous CUL3 mutations. Eight of
the 17 were de novo mutations. Boyden et al. (2012) observed that the
CUL3 mutations identified in their cohort all clustered in sites
implicated in splicing of exon 9, including the intron 8 splice acceptor
(n = 4), the intron 9 splice donor (n = 5), the putative intron 8 splice
branch site (n = 5), and a putative splice enhancer in exon 9 (n = 3,
within a TTGGA(T/A)) splice enhancer consensus sequence.
GENOTYPE/PHENOTYPE CORRELATIONS
Boyden et al. (2012) observed that families with PHAII due to mutation
in the WNK1 gene (PHA2C; 614492) are significantly less severely
affected than those with mutation in the WNK4 gene (PHA2B; 614491) or
dominant or recessive mutation in the KLHL3 gene (605775; PHA2D,
614495), and all are less severely affected than those with dominant
mutation in the CUL3 gene (PHA2E).
*FIELD* RF
1. Boyden, L. M.; Choi, M.; Choate, K. A.; Nelson-Williams, C. J.;
Farhi, A.; Toka, H. R.; Tikhonova, I. R.; Bjornson, R.; Mane, S. M.;
Colussi, G.; Lebel, M.; Gordon, R. D.; and 34 others: Mutations
in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature 482:
98-102, 2012.
*FIELD* CS
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Vascular];
Hypertension
METABOLIC FEATURES:
Hyperchloremic metabolic acidosis (HCO3 15.5 +/- 2.0 mM)
LABORATORY ABNORMALITIES:
Hyperkalemia (7.5 +/- 0.9 mM);
Hyperchloremia (mean 114 mM)
MISCELLANEOUS:
21 patients from 17 kindreds reported (as of February 2012);
Age at diagnosis 9 +/- 6 years;
94% develop hypertension at 18 years of age or less;
Responsive to thiazide diuretics
MOLECULAR BASIS:
Caused by mutation in the cullin 3 gene (CUL3, 603136.0001)
*FIELD* CD
Ada Hamosh: 2/27/2012
*FIELD* ED
joanna: 02/27/2012
*FIELD* CN
Marla J. F. O'Neill - updated: 05/14/2012
*FIELD* CD
Ada Hamosh: 2/24/2012
*FIELD* ED
carol: 05/14/2012
joanna: 2/28/2012
alopez: 2/27/2012
*RECORD*
*FIELD* NO
614496
*FIELD* TI
#614496 PSEUDOHYPOALDOSTERONISM, TYPE IIE; PHA2E
*FIELD* TX
A number sign (#) is used with this entry because
read morepseudohypoaldosteronism type IIE (PHA2E) is caused by heterozygous
mutation in the CUL3 gene (603136) on chromosome 2q36.
For a phenotypic description and a discussion of genetic heterogeneity
of pseudohypoaldosteronism type II, see PHA2A (145260).
CLINICAL FEATURES
Boyden et al. (2012) studied a cohort of 52 PHAII kindreds, including
126 affected subjects with renal hyperkalemia and otherwise normal renal
function; hypertension and acidosis were present in 71% and 82%,
respectively. They detected 21 affected individuals from 17 kindreds
with mutation in the CUL3 gene. The mean age at diagnosis or referral
was 9 +/- 6 years, mean potassium was 7.5 +/- 0.9, and mean bicarbonate
was 15.5 +/- 2.0. Hypertension was present in 94% of patients at or
before 18 years of age. The CUL3 mutation patients had by far the most
severe manifestations of PHAII compared to patients with other
mutations.
CLINICAL MANAGEMENT
Thiazide diuretics correct abnormalities in virtually all PHAII subjects
(Boyden et al., 2012).
MOLECULAR GENETICS
After identifying mutations in the KLHL3 gene (605775) in kindreds with
PHAII (see 614495), Boyden et al. (2012) considered CUL3, the presumed
functional partner of KLHL3, as a candidate. Sequencing CUL3 in 21 index
patients revealed 17 with novel heterozygous CUL3 mutations. Eight of
the 17 were de novo mutations. Boyden et al. (2012) observed that the
CUL3 mutations identified in their cohort all clustered in sites
implicated in splicing of exon 9, including the intron 8 splice acceptor
(n = 4), the intron 9 splice donor (n = 5), the putative intron 8 splice
branch site (n = 5), and a putative splice enhancer in exon 9 (n = 3,
within a TTGGA(T/A)) splice enhancer consensus sequence.
GENOTYPE/PHENOTYPE CORRELATIONS
Boyden et al. (2012) observed that families with PHAII due to mutation
in the WNK1 gene (PHA2C; 614492) are significantly less severely
affected than those with mutation in the WNK4 gene (PHA2B; 614491) or
dominant or recessive mutation in the KLHL3 gene (605775; PHA2D,
614495), and all are less severely affected than those with dominant
mutation in the CUL3 gene (PHA2E).
*FIELD* RF
1. Boyden, L. M.; Choi, M.; Choate, K. A.; Nelson-Williams, C. J.;
Farhi, A.; Toka, H. R.; Tikhonova, I. R.; Bjornson, R.; Mane, S. M.;
Colussi, G.; Lebel, M.; Gordon, R. D.; and 34 others: Mutations
in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature 482:
98-102, 2012.
*FIELD* CS
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Vascular];
Hypertension
METABOLIC FEATURES:
Hyperchloremic metabolic acidosis (HCO3 15.5 +/- 2.0 mM)
LABORATORY ABNORMALITIES:
Hyperkalemia (7.5 +/- 0.9 mM);
Hyperchloremia (mean 114 mM)
MISCELLANEOUS:
21 patients from 17 kindreds reported (as of February 2012);
Age at diagnosis 9 +/- 6 years;
94% develop hypertension at 18 years of age or less;
Responsive to thiazide diuretics
MOLECULAR BASIS:
Caused by mutation in the cullin 3 gene (CUL3, 603136.0001)
*FIELD* CD
Ada Hamosh: 2/27/2012
*FIELD* ED
joanna: 02/27/2012
*FIELD* CN
Marla J. F. O'Neill - updated: 05/14/2012
*FIELD* CD
Ada Hamosh: 2/24/2012
*FIELD* ED
carol: 05/14/2012
joanna: 2/28/2012
alopez: 2/27/2012