ID CUL2_HUMAN Reviewed; 745 AA. AC Q13617; B3KT95; B7Z6K8; D3DRY6; G3V1S2; O00200; Q5T2B6; Q9UNF9; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 14-AUG-2001, sequence version 2. DT 27-MAR-2024, entry version 209. DE RecName: Full=Cullin-2; DE Short=CUL-2; GN Name=CUL2 {ECO:0000312|HGNC:HGNC:2552}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT SER-109, IDENTIFICATION IN RP COMPLEX WITH VHL AND ELONGIN BC, AND FUNCTION. RC TISSUE=Kidney; RX PubMed=9122164; DOI=10.1073/pnas.94.6.2156; RA Pause A., Lee S., Worrel R., Chen D.Y.T., Burgess W.H., Linehan W.M., RA Klausner R.D.; RT "The von Hippel-Lindau tumor-suppressor gene product forms a stable complex RT with human CUL-2, a member of the Cdc53 family of proteins."; RL Proc. Natl. Acad. Sci. U.S.A. 94:2156-2161(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT SER-109, MUTAGENESIS OF RP LYS-621; LYS-689 AND LYS-719, AND NEDDYLATION AT LYS-689. RC TISSUE=Brain; RX PubMed=10092517; DOI=10.1006/bbrc.1999.0339; RA Wada H., Yeh E.T.H., Kamitani T.; RT "Identification of NEDD8-conjugation site in human cullin-2."; RL Biochem. Biophys. Res. Commun. 257:100-105(1999). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Prostate; 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., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., 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., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA 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 [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164054; DOI=10.1038/nature02462; RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P., RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 10."; RL Nature 429:375-381(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain, and Skin; 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 project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] OF 95-745. 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 novel RT gene family."; RL Cell 85:829-839(1996). RN [8] 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 an RT associated ubiquitin ligase activity."; RL Mol. Cell 3:535-541(1999). RN [9] RP FUNCTION, AND IDENTIFICATION IN CBC(VHL) COMPLEX. RX PubMed=10973499; DOI=10.1073/pnas.190332597; RA Kamura T., Sato S., Iwai K., Czyzyk-Krzeska M., Conaway R.C., Conaway J.W.; RT "Activation of HIF1alpha ubiquitination by a reconstituted von Hippel- RT Lindau (VHL) tumor suppressor complex."; RL Proc. Natl. Acad. Sci. U.S.A. 97:10430-10435(2000). RN [10] RP IDENTIFICATION IN COMPLEX WITH VHL; ELONGIN BC AND RBX1, AND FUNCTION. RX PubMed=11384984; DOI=10.1074/jbc.m103093200; RA Kamura T., Burian D., Yan Q., Schmidt S.L., Lane W.S., Querido E., RA Branton P.E., Shilatifard A., Conaway R.C., Conaway J.W.; RT "Muf1, a novel elongin BC-interacting leucine-rich repeat protein that can RT assemble with Cul5 and Rbx1 to reconstitute a ubiquitin ligase."; RL J. Biol. Chem. 276:29748-29753(2001). RN [11] RP IDENTIFICATION IN E3 UBIQUITIN-PROTEIN LIGASE COMPLEX WITH MED8. RX PubMed=12149480; DOI=10.1073/pnas.162424199; RA Brower C.S., Sato S., Tomomori-Sato C., Kamura T., Pause A., Stearman R., RA Klausner R.D., Malik S., Lane W.S., Sorokina I., Roeder R.G., Conaway J.W., RA Conaway R.C.; RT "Mammalian mediator subunit mMED8 is an Elongin BC-interacting protein that RT can assemble with Cul2 and Rbx1 to reconstitute a ubiquitin ligase."; RL Proc. Natl. Acad. Sci. U.S.A. 99:10353-10358(2002). RN [12] RP FUNCTION, AND 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 activity."; RL J. Biol. Chem. 278:15905-15910(2003). 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 by RT NEDD8."; RL Oncogene 18:6829-6834(1999). RN [14] RP INTERACTION WITH LRR1 AND FEM1B. RX PubMed=15601820; DOI=10.1101/gad.1252404; RA Kamura T., Maenaka K., Kotoshiba S., Matsumoto M., Kohda D., Conaway R.C., RA Conaway J.W., Nakayama K.I.; RT "VHL-box and SOCS-box domains determine binding specificity for Cul2-Rbx1 RT and Cul5-Rbx2 modules of ubiquitin ligases."; RL Genes Dev. 18:3055-3065(2004). RN [15] RP IDENTIFICATION IN COMPLEX WITH ELOC AND ZYG11B, AND IDENTIFICATION IN RP COMPLEX WITH ELOB; ELOC AND ZER1. RX PubMed=17304241; DOI=10.1038/sj.embor.7400895; RA Vasudevan S., Starostina N.G., Kipreos E.T.; RT "The Caenorhabditis elegans cell-cycle regulator ZYG-11 defines a conserved RT family of CUL-2 complex components."; RL EMBO Rep. 8:279-286(2007). RN [16] RP INTERACTION WITH HRSV VIRUS PROTEIN NS1 (MICROBIAL INFECTION). RX PubMed=17251292; DOI=10.1128/jvi.02303-06; RA Elliott J., Lynch O.T., Suessmuth Y., Qian P., Boyd C.R., Burrows J.F., RA Buick R., Stevenson N.J., Touzelet O., Gadina M., Power U.F., RA Johnston J.A.; RT "Respiratory syncytial virus NS1 protein degrades STAT2 by using the RT Elongin-Cullin E3 ligase."; RL J. Virol. 81:3428-3436(2007). RN [17] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-661, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [18] RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-393, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19608861; DOI=10.1126/science.1175371; RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., RA Olsen J.V., Mann M.; RT "Lysine acetylation targets protein complexes and co-regulates major RT cellular functions."; RL Science 325:834-840(2009). RN [19] 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., Buerckstuemmer T., RA 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 [20] RP INTERACTS WITH KLHDC10. RX PubMed=23102700; DOI=10.1016/j.molcel.2012.09.018; RA Sekine Y., Hatanaka R., Watanabe T., Sono N., Iemura S., Natsume T., RA Kuranaga E., Miura M., Takeda K., Ichijo H.; RT "The Kelch repeat protein KLHDC10 regulates oxidative stress-induced ASK1 RT activation by suppressing PP5."; RL Mol. Cell 48:692-704(2012). RN [21] RP IDENTIFICATION IN A COMPLEX WITH LIMD1; EGLN1/PHD2; VHL AND ELOB. RX PubMed=22286099; DOI=10.1038/ncb2424; RA Foxler D.E., Bridge K.S., James V., Webb T.M., Mee M., Wong S.C., Feng Y., RA Constantin-Teodosiu D., Petursdottir T.E., Bjornsson J., Ingvarsson S., RA Ratcliffe P.J., Longmore G.D., Sharp T.V.; RT "The LIMD1 protein bridges an association between the prolyl hydroxylases RT and VHL to repress HIF-1 activity."; RL Nat. Cell Biol. 14:201-208(2012). RN [22] RP FUNCTION, INTERACTION WITH ARIH1, AND NEDDYLATION. RX PubMed=24076655; DOI=10.1038/emboj.2013.209; RA Kelsall I.R., Duda D.M., Olszewski J.L., Hofmann K., Knebel A., RA Langevin F., Wood N., Wightman M., Schulman B.A., Alpi A.F.; RT "TRIAD1 and HHARI bind to and are activated by distinct neddylated Cullin- RT RING ligase complexes."; RL EMBO J. 32:2848-2860(2013). RN [23] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-661, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [24] RP INTERACTION WITH DCUN1D1, AND COMPONENT OF VCB COMPLEX. RX PubMed=23401859; DOI=10.1128/mcb.01342-12; RA Heir P., Sufan R.I., Greer S.N., Poon B.P., Lee J.E., Ohh M.; RT "DCNL1 functions as a substrate sensor and activator of cullin 2-RING RT ligase."; RL Mol. Cell. Biol. 33:1621-1631(2013). RN [25] RP INTERACTION WITH DCUN1D1; DCUN1D2; DCUN1D3; DCUN1D4 AND DCUN1D5. RX PubMed=23201271; DOI=10.1016/j.str.2012.10.013; RA Monda J.K., Scott D.C., Miller D.J., Lydeard J., King D., Harper J.W., RA Bennett E.J., Schulman B.A.; RT "Structural conservation of distinctive N-terminal acetylation-dependent RT interactions across a family of mammalian NEDD8 ligation enzymes."; RL Structure 21:42-53(2013). RN [26] RP INTERACTION WITH DCUN1D5. RX PubMed=24192928; DOI=10.1158/1078-0432.ccr-13-1252; RA Bommelje C.C., Weeda V.B., Huang G., Shah K., Bains S., Buss E., Shaha M., RA Goenen M., Ghossein R., Ramanathan S.Y., Singh B.; RT "Oncogenic function of SCCRO5/DCUN1D5 requires its Neddylation E3 activity RT and nuclear localization."; RL Clin. Cancer Res. 20:372-381(2014). RN [27] RP FUNCTION, INTERACTION WITH ARIH1, AND NEDDYLATION. RX PubMed=27565346; DOI=10.1016/j.cell.2016.07.027; RA Scott D.C., Rhee D.Y., Duda D.M., Kelsall I.R., Olszewski J.L., Paulo J.A., RA de Jong A., Ovaa H., Alpi A.F., Harper J.W., Schulman B.A.; RT "Two distinct types of E3 ligases work in unison to regulate substrate RT ubiquitylation."; RL Cell 166:1198-1214(2016). RN [28] RP INTERACTION WITH DCUN1D1; DCUN1D2; DCUN1D3; DCUN1D4 AND DCUN1D5. RX PubMed=26906416; DOI=10.1242/jcs.181784; RA Keuss M.J., Thomas Y., Mcarthur R., Wood N.T., Knebel A., Kurz T.; RT "Characterization of the mammalian family of DCN-type NEDD8 E3 ligases."; RL J. Cell Sci. 129:1441-1454(2016). RN [29] RP FUNCTION, AND PATHWAY. RX PubMed=26138980; DOI=10.1126/science.aab0515; RA Lin H.C., Ho S.C., Chen Y.Y., Khoo K.H., Hsu P.H., Yen H.C.; RT "SELENOPROTEINS. CRL2 aids elimination of truncated selenoproteins produced RT by failed UGA/Sec decoding."; RL Science 349:91-95(2015). RN [30] RP FUNCTION, PATHWAY, AND IDENTIFICATION IN A CRL2 E3 UBIQUITIN-PROTEIN LIGASE RP COMPLEX. RX PubMed=29779948; DOI=10.1016/j.cell.2018.04.028; RA Koren I., Timms R.T., Kula T., Xu Q., Li M.Z., Elledge S.J.; RT "The eukaryotic proteome is shaped by E3 ubiquitin ligases targeting C- RT terminal degrons."; RL Cell 173:1622-1635(2018). RN [31] RP FUNCTION, PATHWAY, AND IDENTIFICATION IN A CRL2 E3 UBIQUITIN-PROTEIN LIGASE RP COMPLEX. RX PubMed=29775578; DOI=10.1016/j.molcel.2018.04.006; RA Lin H.C., Yeh C.W., Chen Y.F., Lee T.T., Hsieh P.Y., Rusnac D.V., Lin S.Y., RA Elledge S.J., Zheng N., Yen H.S.; RT "C-terminal end-directed protein elimination by CRL2 ubiquitin ligases."; RL Mol. Cell 70:602-613(2018). RN [32] {ECO:0007744|PDB:7PLO} RP STRUCTURE BY ELECTRON MICROSCOPY (2.80 ANGSTROMS) IN COMPLEX WITH RP REPLISOME. RX PubMed=34700328; DOI=10.1038/s41586-021-04145-3; RA Jenkyn-Bedford M., Jones M.L., Baris Y., Labib K.P.M., Cannone G., RA Yeeles J.T.P., Deegan T.D.; RT "A conserved mechanism for regulating replisome disassembly in RT eukaryotes."; RL Nature 600:743-747(2021). CC -!- FUNCTION: Core component of multiple cullin-RING-based ECS (ElonginB/C- CC CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complexes, which CC mediate the ubiquitination of target proteins (PubMed:11384984, CC PubMed:26138980, PubMed:29779948, PubMed:29775578). CUL2 may serve as a CC rigid scaffold in the complex and may contribute to catalysis through CC positioning of the substrate and the ubiquitin-conjugating enzyme CC (PubMed:9122164, PubMed:10973499, PubMed:11384984, PubMed:12609982, CC PubMed:24076655). The E3 ubiquitin-protein ligase activity of the CC complex is dependent on the neddylation of the cullin subunit and is CC inhibited by the association of the deneddylated cullin subunit with CC TIP120A/CAND1 (PubMed:12609982, PubMed:24076655, PubMed:27565346). The CC functional specificity of the ECS complex depends on the substrate CC recognition component (PubMed:9122164, PubMed:10973499, CC PubMed:26138980, PubMed:29779948, PubMed:29775578). ECS(VHL) mediates CC the ubiquitination of hypoxia-inducible factor (HIF) (PubMed:9122164, CC PubMed:10973499). A number of ECS complexes (containing either KLHDC2, CC KLHDC3, KLHDC10, APPBP2, FEM1A, FEM1B or FEM1C as substrate-recognition CC component) are part of the DesCEND (destruction via C-end degrons) CC pathway, which recognizes a C-degron located at the extreme C terminus CC of target proteins, leading to their ubiquitination and degradation CC (PubMed:26138980, PubMed:29779948, PubMed:29775578). ECS complexes and CC ARIH1 collaborate in tandem to mediate ubiquitination of target CC proteins (PubMed:27565346). ECS(LRR1) ubiquitinates MCM7 and promotes CC CMG replisome disassembly by VCP and chromatin extraction during S- CC phase (By similarity). {ECO:0000250|UniProtKB:Q9D4H8, CC ECO:0000269|PubMed:10973499, ECO:0000269|PubMed:11384984, CC ECO:0000269|PubMed:12609982, ECO:0000269|PubMed:24076655, CC ECO:0000269|PubMed:26138980, ECO:0000269|PubMed:27565346, CC ECO:0000269|PubMed:29775578, ECO:0000269|PubMed:29779948, CC ECO:0000269|PubMed:9122164}. CC -!- PATHWAY: Protein modification; protein ubiquitination. CC {ECO:0000269|PubMed:26138980, ECO:0000269|PubMed:29775578, CC ECO:0000269|PubMed:29779948}. CC -!- SUBUNIT: Component of multiple ECS (Elongin BC-CUL2/5-SOCS-box protein) CC E3 ubiquitin-protein ligase complexes formed of CUL2, Elongin BC (ELOB CC and ELOC), RBX1 and a variable substrate-specific adapter CC (PubMed:9122164, PubMed:10973499, PubMed:11384984, PubMed:26138980, CC PubMed:29779948, PubMed:29775578). Component of the ECS(VHL) or CC CBC(VHL) complex containing VHL (PubMed:9122164, PubMed:10973499, CC PubMed:11384984). Component of the ECS(MED8) complex with the probable CC substrate recognition component MED8 (PubMed:12149480). Component of CC multiple ECS complexes part of the DesCEND (destruction via C-end CC degrons) pathway, which contain either KLHDC2, KLHDC3, KLHDC10, APPBP2, CC FEM1A, FEM1B or FEM1C as substrate-recognition component CC (PubMed:23102700, PubMed:26138980, PubMed:29779948, PubMed:29775578). CC Component of the ECS(LRR1) complex with the probable substrate CC recognition component LRR1 (PubMed:15601820, PubMed:34700328). CC Component of a probable ECS E3 ubiquitin-protein ligase complex CC containing CUL2, RBX1, ELOB, ELOC and FEM1B (PubMed:15601820). Part of CC an E3 ubiquitin-protein ligase complex including ZYG11B, CUL2 and CC Elongin BC (PubMed:17304241). Part of an E3 ubiquitin-protein ligase CC complex including ZER1, CUL2 and Elongin BC (PubMed:17304241). CC Interacts with RBX1, RNF7, FEM1B and TIP120A/CAND1 (PubMed:10230407, CC PubMed:12609982). Found in a complex composed of LIMD1, VHL, CC EGLN1/PHD2, ELOB and CUL2 (PubMed:22286099). Interacts (when CC neddylated) with ARIH1; leading to activate the E3 ligase activity of CC ARIH1 (PubMed:24076655, PubMed:27565346). Interacts (unneddylated form) CC with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5; these interactions CC promote the cullin neddylation (PubMed:23401859, PubMed:23201271, CC PubMed:24192928, PubMed:26906416). Component of VCB (elongins CC BC/CUL2/VHL) complex that contains at least DCUN1D1, CUL2 and VHL; this CC complex triggers CUL2 neddylation and consequently cullin ring ligase CC (CRL) substrates polyubiquitylation (PubMed:23401859). CC {ECO:0000269|PubMed:10230407, ECO:0000269|PubMed:10973499, CC ECO:0000269|PubMed:11384984, ECO:0000269|PubMed:12149480, CC ECO:0000269|PubMed:12609982, ECO:0000269|PubMed:15601820, CC ECO:0000269|PubMed:17304241, ECO:0000269|PubMed:22286099, CC ECO:0000269|PubMed:23102700, ECO:0000269|PubMed:23201271, CC ECO:0000269|PubMed:23401859, ECO:0000269|PubMed:24076655, CC ECO:0000269|PubMed:24192928, ECO:0000269|PubMed:26138980, CC ECO:0000269|PubMed:26906416, ECO:0000269|PubMed:27565346, CC ECO:0000269|PubMed:29775578, ECO:0000269|PubMed:29779948, CC ECO:0000269|PubMed:34700328, ECO:0000269|PubMed:9122164}. CC -!- SUBUNIT: (Microbial infection) Interacts with human respiratory CC syncytial virus (HRSV) protein NS1. {ECO:0000269|PubMed:17251292}. CC -!- INTERACTION: CC Q13617; Q86VP6: CAND1; NbExp=3; IntAct=EBI-456179, EBI-456077; CC Q13617; Q8N668: COMMD1; NbExp=6; IntAct=EBI-456179, EBI-1550112; CC Q13617; Q15369: ELOC; NbExp=10; IntAct=EBI-456179, EBI-301231; CC Q13617; P08238: HSP90AB1; NbExp=2; IntAct=EBI-456179, EBI-352572; CC Q13617; Q9BQ90: KLHDC3; NbExp=8; IntAct=EBI-456179, EBI-1055396; CC Q13617; Q15048: LRRC14; NbExp=6; IntAct=EBI-456179, EBI-2510124; CC Q13617; P62877: RBX1; NbExp=8; IntAct=EBI-456179, EBI-398523; CC Q13617; O94888: UBXN7; NbExp=20; IntAct=EBI-456179, EBI-1993627; CC Q13617; P40337: VHL; NbExp=16; IntAct=EBI-456179, EBI-301246; CC Q13617; Q9C0D3: ZYG11B; NbExp=4; IntAct=EBI-456179, EBI-1811414; CC Q13617; P12504: vif; Xeno; NbExp=6; IntAct=EBI-456179, EBI-779991; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q9D4H8}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q13617-1; Sequence=Displayed; CC Name=2; CC IsoId=Q13617-2; Sequence=VSP_044498; CC -!- PTM: Neddylated; which enhances the ubiquitination activity of ECS CC (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase CC complexes. CBC(VHL) complex formation seems to promote neddylation. CC Deneddylated via its interaction with the COP9 signalosome (CSN) CC complex (By similarity). {ECO:0000250|UniProtKB:Q9D4H8, CC ECO:0000269|PubMed:24076655, ECO:0000269|PubMed:27565346}. CC -!- SIMILARITY: Belongs to the cullin family. {ECO:0000255|PROSITE- CC ProRule:PRU00330}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U83410; AAC51190.1; -; mRNA. DR EMBL; AF126404; AAD23581.1; -; mRNA. DR EMBL; AK095217; BAG53007.1; -; mRNA. DR EMBL; AK300491; BAH13294.1; -; mRNA. DR EMBL; AL392046; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471072; EAW85924.1; -; Genomic_DNA. DR EMBL; CH471072; EAW85925.1; -; Genomic_DNA. DR EMBL; CH471072; EAW85926.1; -; Genomic_DNA. DR EMBL; CH471072; EAW85927.1; -; Genomic_DNA. DR EMBL; CH471072; EAW85928.1; -; Genomic_DNA. DR EMBL; BC009591; AAH09591.1; -; mRNA. DR EMBL; BC110901; AAI10902.1; -; mRNA. DR EMBL; U58088; AAC50545.1; -; mRNA. DR CCDS; CCDS55709.1; -. [Q13617-2] DR CCDS; CCDS7179.1; -. [Q13617-1] DR RefSeq; NP_001185706.1; NM_001198777.1. [Q13617-1] DR RefSeq; NP_001185707.1; NM_001198778.1. [Q13617-2] DR RefSeq; NP_001185708.1; NM_001198779.1. DR RefSeq; NP_003582.2; NM_003591.3. [Q13617-1] DR RefSeq; XP_011518049.1; XM_011519747.1. [Q13617-1] DR PDB; 4WQO; X-ray; 3.20 A; D=1-163. DR PDB; 5N4W; X-ray; 3.90 A; A=1-745. DR PDB; 6R6H; EM; 8.40 A; O=1-745. DR PDB; 6R7F; EM; 8.20 A; O=1-745. DR PDB; 6R7H; EM; 8.80 A; O=1-654. DR PDB; 6R7I; EM; 5.90 A; O=1-745. DR PDB; 6R7N; EM; 6.50 A; O=1-745. DR PDB; 7PLO; EM; 2.80 A; S=1-745. DR PDB; 8JAL; EM; 3.30 A; E/I=2-745. DR PDB; 8JAQ; EM; 3.26 A; E/I/L/U=2-745. DR PDB; 8JAR; EM; 3.30 A; E/I=2-745. DR PDB; 8JAS; EM; 3.54 A; E/I/L/U=2-745. DR PDB; 8JAU; EM; 3.22 A; E/I=2-745. DR PDB; 8JAV; EM; 3.44 A; E/I/L/U=2-745. DR PDB; 8QU8; EM; 3.50 A; D=2-745. DR PDBsum; 4WQO; -. DR PDBsum; 5N4W; -. DR PDBsum; 6R6H; -. DR PDBsum; 6R7F; -. DR PDBsum; 6R7H; -. DR PDBsum; 6R7I; -. DR PDBsum; 6R7N; -. DR PDBsum; 7PLO; -. DR PDBsum; 8JAL; -. DR PDBsum; 8JAQ; -. DR PDBsum; 8JAR; -. DR PDBsum; 8JAS; -. DR PDBsum; 8JAU; -. DR PDBsum; 8JAV; -. DR PDBsum; 8QU8; -. DR AlphaFoldDB; Q13617; -. DR EMDB; EMD-13494; -. DR EMDB; EMD-36129; -. DR EMDB; EMD-36131; -. DR EMDB; EMD-36132; -. DR EMDB; EMD-36133; -. DR EMDB; EMD-36134; -. DR EMDB; EMD-36135; -. DR EMDB; EMD-4736; -. DR EMDB; EMD-4739; -. DR EMDB; EMD-4741; -. DR EMDB; EMD-4742; -. DR EMDB; EMD-4744; -. DR SMR; Q13617; -. DR BioGRID; 114031; 611. DR ComplexPortal; CPX-2214; LRR1-Elongin C-Elongin B E3 ubiquitin ligase complex. DR ComplexPortal; CPX-2217; FEM1A-Elongin C-Elongin B E3 ubiquitin ligase complex. DR ComplexPortal; CPX-2218; FEB1B-Elongin C-Elongin B E3 ubiquitin ligase complex. DR ComplexPortal; CPX-2219; FEB1C-Elongin C-Elongin B E3 ubiquitin ligase complex. DR ComplexPortal; CPX-2220; ZYG11B-Elongin C-Elongin B E3 ubiquitin ligase complex. DR ComplexPortal; CPX-2221; APPBP2-Elongin C-Elongin B E3 ubiquitin ligase complex. DR ComplexPortal; CPX-2222; ZER1-Elongin C-Elongin B E3 ubiquitin ligase complex. DR ComplexPortal; CPX-2223; KLHDC10-Elongin C-Elongin B E3 ubiquitin ligase complex. DR ComplexPortal; CPX-2226; KLHDC2-Elongin C-Elongin B E3 ubiquitin ligase complex. DR ComplexPortal; CPX-2228; KLHDC3-Elongin C-Elongin B E3 ubiquitin ligase complex. DR ComplexPortal; CPX-2229; PRAME-Elongin C-Elongin B E3 ubiquitin ligase complex. DR ComplexPortal; CPX-2250; VHL-Elongin C-Elongin B E3 ubiquitin ligase complex. DR CORUM; Q13617; -. DR DIP; DIP-31612N; -. DR IntAct; Q13617; 383. DR MINT; Q13617; -. DR STRING; 9606.ENSP00000414095; -. DR BindingDB; Q13617; -. DR GlyGen; Q13617; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q13617; -. DR MetOSite; Q13617; -. DR PhosphoSitePlus; Q13617; -. DR SwissPalm; Q13617; -. DR BioMuta; CUL2; -. DR DMDM; 19863260; -. DR EPD; Q13617; -. DR jPOST; Q13617; -. DR MassIVE; Q13617; -. DR MaxQB; Q13617; -. DR PaxDb; 9606-ENSP00000444856; -. DR PeptideAtlas; Q13617; -. DR ProteomicsDB; 32423; -. DR ProteomicsDB; 59605; -. [Q13617-1] DR Pumba; Q13617; -. DR Antibodypedia; 3631; 557 antibodies from 42 providers. DR DNASU; 8453; -. DR Ensembl; ENST00000374748.5; ENSP00000363880.1; ENSG00000108094.17. [Q13617-1] DR Ensembl; ENST00000374749.8; ENSP00000363881.3; ENSG00000108094.17. [Q13617-1] DR Ensembl; ENST00000374751.7; ENSP00000363883.3; ENSG00000108094.17. [Q13617-1] DR Ensembl; ENST00000421317.5; ENSP00000414095.2; ENSG00000108094.17. [Q13617-2] DR Ensembl; ENST00000673636.2; ENSP00000501215.1; ENSG00000108094.17. [Q13617-1] DR Ensembl; ENST00000690393.1; ENSP00000510691.1; ENSG00000108094.17. [Q13617-1] DR Ensembl; ENST00000691974.1; ENSP00000508908.1; ENSG00000108094.17. [Q13617-1] DR GeneID; 8453; -. DR KEGG; hsa:8453; -. DR MANE-Select; ENST00000374749.8; ENSP00000363881.3; NM_003591.4; NP_003582.2. DR UCSC; uc001ixv.4; human. [Q13617-1] DR AGR; HGNC:2552; -. DR CTD; 8453; -. DR DisGeNET; 8453; -. DR GeneCards; CUL2; -. DR HGNC; HGNC:2552; CUL2. DR HPA; ENSG00000108094; Low tissue specificity. DR MIM; 603135; gene. DR neXtProt; NX_Q13617; -. DR OpenTargets; ENSG00000108094; -. DR PharmGKB; PA27048; -. DR VEuPathDB; HostDB:ENSG00000108094; -. DR eggNOG; KOG2284; Eukaryota. DR GeneTree; ENSGT00940000154926; -. DR HOGENOM; CLU_004747_6_1_1; -. DR InParanoid; Q13617; -. DR OrthoDB; 5474206at2759; -. DR PhylomeDB; Q13617; -. DR TreeFam; TF101152; -. DR BRENDA; 2.3.2.32; 2681. DR PathwayCommons; Q13617; -. DR Reactome; R-HSA-1234176; Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha. DR Reactome; R-HSA-8951664; Neddylation. DR Reactome; R-HSA-9010553; Regulation of expression of SLITs and ROBOs. DR Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation. DR SignaLink; Q13617; -. DR SIGNOR; Q13617; -. DR UniPathway; UPA00143; -. DR BioGRID-ORCS; 8453; 481 hits in 1223 CRISPR screens. DR ChiTaRS; CUL2; human. DR GeneWiki; CUL2; -. DR GenomeRNAi; 8453; -. DR Pharos; Q13617; Tbio. DR PRO; PR:Q13617; -. DR Proteomes; UP000005640; Chromosome 10. DR RNAct; Q13617; Protein. DR Bgee; ENSG00000108094; Expressed in sperm and 198 other cell types or tissues. DR ExpressionAtlas; Q13617; baseline and differential. DR GO; GO:0031462; C:Cul2-RING ubiquitin ligase complex; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0005730; C:nucleolus; IEA:Ensembl. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0019005; C:SCF ubiquitin ligase complex; IBA:GO_Central. DR GO; GO:0030891; C:VCB complex; IEA:Ensembl. DR GO; GO:0044877; F:protein-containing complex binding; IEA:Ensembl. DR GO; GO:0030674; F:protein-macromolecule adaptor activity; IBA:GO_Central. DR GO; GO:0160072; F:ubiquitin ligase complex scaffold activity; IDA:UniProt. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IDA:UniProtKB. DR GO; GO:0004842; F:ubiquitin-protein transferase activity; TAS:Reactome. DR GO; GO:0000082; P:G1/S transition of mitotic cell cycle; TAS:ProtInc. DR GO; GO:0097193; P:intrinsic apoptotic signaling pathway; TAS:ProtInc. DR GO; GO:0016567; P:protein ubiquitination; IBA:GO_Central. DR GO; GO:0031146; P:SCF-dependent proteasomal ubiquitin-dependent protein catabolic process; IBA:GO_Central. DR GO; GO:0140627; P:ubiquitin-dependent protein catabolic process via the C-end degron rule pathway; IDA:UniProt. DR Gene3D; 1.20.1310.10; Cullin Repeats; 4. DR Gene3D; 1.10.10.10; Winged helix-like DNA-binding domain superfamily/Winged helix DNA-binding domain; 1. DR InterPro; IPR045093; Cullin. DR InterPro; IPR016157; Cullin_CS. DR InterPro; IPR016158; Cullin_homology. DR InterPro; IPR036317; Cullin_homology_sf. DR InterPro; IPR001373; Cullin_N. DR InterPro; IPR019559; Cullin_neddylation_domain. DR InterPro; IPR016159; Cullin_repeat-like_dom_sf. DR InterPro; IPR036388; WH-like_DNA-bd_sf. DR InterPro; IPR036390; WH_DNA-bd_sf. DR PANTHER; PTHR11932; CULLIN; 1. DR PANTHER; PTHR11932:SF177; CULLIN-2; 1. DR Pfam; PF00888; Cullin; 1. DR Pfam; PF10557; Cullin_Nedd8; 1. DR SMART; SM00182; CULLIN; 1. DR SMART; SM00884; Cullin_Nedd8; 1. DR SUPFAM; SSF75632; Cullin homology domain; 1. DR SUPFAM; SSF74788; Cullin repeat-like; 1. DR SUPFAM; SSF46785; Winged helix' DNA-binding domain; 1. DR PROSITE; PS01256; CULLIN_1; 1. DR PROSITE; PS50069; CULLIN_2; 1. DR Genevisible; Q13617; HS. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; Host-virus interaction; KW Isopeptide bond; Nucleus; Phosphoprotein; Reference proteome; KW Ubl conjugation; Ubl conjugation pathway. FT CHAIN 1..745 FT /note="Cullin-2" FT /id="PRO_0000119790" FT MOD_RES 393 FT /note="N6-acetyllysine" FT /evidence="ECO:0007744|PubMed:19608861" FT MOD_RES 661 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT CROSSLNK 689 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in NEDD8)" FT /evidence="ECO:0000269|PubMed:10092517, FT ECO:0000269|PubMed:10597293" FT VAR_SEQ 1 FT /note="M -> MYRVTWSTFWLRFQHYTCTM (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_044498" FT VARIANT 109 FT /note="N -> S" FT /evidence="ECO:0000269|PubMed:10092517, FT ECO:0000269|PubMed:9122164" FT /id="VAR_011374" FT MUTAGEN 621 FT /note="K->R: No effect on conjugation with NEDD8." FT /evidence="ECO:0000269|PubMed:10092517" FT MUTAGEN 689 FT /note="K->R: Loss of conjugation with NEDD8." FT /evidence="ECO:0000269|PubMed:10092517" FT MUTAGEN 719 FT /note="K->R: No effect on conjugation with NEDD8." FT /evidence="ECO:0000269|PubMed:10092517" FT CONFLICT 20 FT /note="T -> I (in Ref. 3; BAH13294)" FT /evidence="ECO:0000305" FT CONFLICT 95..98 FT /note="SKGA -> IRHE (in Ref. 7; AAC50545)" FT /evidence="ECO:0000305" FT CONFLICT 681 FT /note="Q -> H (in Ref. 7; AAC50545)" FT /evidence="ECO:0000305" FT HELIX 10..25 FT /evidence="ECO:0007829|PDB:4WQO" FT HELIX 32..47 FT /evidence="ECO:0007829|PDB:4WQO" FT STRAND 49..51 FT /evidence="ECO:0007829|PDB:4WQO" FT HELIX 54..77 FT /evidence="ECO:0007829|PDB:4WQO" FT HELIX 85..104 FT /evidence="ECO:0007829|PDB:4WQO" FT HELIX 106..112 FT /evidence="ECO:0007829|PDB:4WQO" FT HELIX 139..156 FT /evidence="ECO:0007829|PDB:4WQO" SQ SEQUENCE 745 AA; 86983 MW; 30647248F671AB0E CRC64; MSLKPRVVDF DETWNKLLTT IKAVVMLEYV ERATWNDRFS DIYALCVAYP EPLGERLYTE TKIFLENHVR HLHKRVLESE EQVLVMYHRY WEEYSKGADY MDCLYRYLNT QFIKKNKLTE ADLQYGYGGV DMNEPLMEIG ELALDMWRKL MVEPLQAILI RMLLREIKND RGGEDPNQKV IHGVINSFVH VEQYKKKFPL KFYQEIFESP FLTETGEYYK QEASNLLQES NCSQYMEKVL GRLKDEEIRC RKYLHPSSYT KVIHECQQRM VADHLQFLHA ECHNIIRQEK KNDMANMYVL LRAVSTGLPH MIQELQNHIH DEGLRATSNL TQENMPTLFV ESVLEVHGKF VQLINTVLNG DQHFMSALDK ALTSVVNYRE PKSVCKAPEL LAKYCDNLLK KSAKGMTENE VEDRLTSFIT VFKYIDDKDV FQKFYARMLA KRLIHGLSMS MDSEEAMINK LKQACGYEFT SKLHRMYTDM SVSADLNNKF NNFIKNQDTV IDLGISFQIY VLQAGAWPLT QAPSSTFAIP QELEKSVQMF ELFYSQHFSG RKLTWLHYLC TGEVKMNYLG KPYVAMVTTY QMAVLLAFNN SETVSYKELQ DSTQMNEKEL TKTIKSLLDV KMINHDSEKE DIDAESSFSL NMNFSSKRTK FKITTSMQKD TPQEMEQTRS AVDEDRKMYL QAAIVRIMKA RKVLRHNALI QEVISQSRAR FNPSISMIKK CIEVLIDKQY IERSQASADE YSYVA //