ID CUL2_MOUSE Reviewed; 745 AA.
AC Q9D4H8; Q3TUR8;
DT 07-NOV-2003, integrated into UniProtKB/Swiss-Prot.
DT 07-NOV-2003, sequence version 2.
DT 24-JAN-2024, entry version 171.
DE RecName: Full=Cullin-2;
DE Short=CUL-2;
GN Name=Cul2 {ECO:0000312|MGI:MGI:1918995};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC STRAIN=C57BL/6J; TISSUE=Testis;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC STRAIN=C57BL/6J, and Czech II; TISSUE=Mammary tumor;
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 [3]
RP INTERACTION WITH COPS2.
RX PubMed=11967155; DOI=10.1016/s0960-9822(02)00791-1;
RA Yang X., Menon S., Lykke-Andersen K., Tsuge T., Xiao D., Wang X.,
RA Rodriguez-Suarez R.J., Zhang H., Wei N.;
RT "The COP9 signalosome inhibits p27(kip1) degradation and impedes G1-S phase
RT progression via deneddylation of SCF Cul1.";
RL Curr. Biol. 12:667-672(2002).
RN [4]
RP INTERACTION 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 [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung, Pancreas,
RC Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [6]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-393, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic fibroblast;
RX PubMed=23806337; DOI=10.1016/j.molcel.2013.06.001;
RA Park J., Chen Y., Tishkoff D.X., Peng C., Tan M., Dai L., Xie Z., Zhang Y.,
RA Zwaans B.M., Skinner M.E., Lombard D.B., Zhao Y.;
RT "SIRT5-mediated lysine desuccinylation impacts diverse metabolic
RT pathways.";
RL Mol. Cell 50:919-930(2013).
RN [7]
RP FUNCTION, SUBUNIT, AND SUBCELLULAR LOCATION.
RX PubMed=33590678; DOI=10.15252/embr.202052164;
RA Villa F., Fujisawa R., Ainsworth J., Nishimura K., Lie-A-Ling M.,
RA Lacaud G., Labib K.P.;
RT "CUL2LRR1, TRAIP and p97 control CMG helicase disassembly in the mammalian
RT cell cycle.";
RL EMBO Rep. 22:e52164-e52164(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. 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. The
CC E3 ubiquitin-protein ligase activity of the complex is dependent on the
CC neddylation of the cullin subunit and is inhibited by the association
CC of the deneddylated cullin subunit with TIP120A/CAND1. The functional
CC specificity of the ECS complex depends on the substrate recognition
CC component. ECS(VHL) mediates the ubiquitination of hypoxia-inducible
CC factor (HIF). 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 ECS complexes and ARIH1 collaborate in tandem to mediate ubiquitination
CC of target proteins. ECS(LRR1) ubiquitinates MCM7 and promotes CMG
CC replisome disassembly by VCP and chromatin extraction during S-phase
CC (PubMed:33590678). {ECO:0000250|UniProtKB:Q13617,
CC ECO:0000269|PubMed:33590678}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000269|PubMed:33590678}.
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. Component of
CC the ECS(VHL) or CBC(VHL) complex containing VHL. Component of the
CC ECS(MED8) complex with the probable substrate recognition component
CC MED8. Component of multiple ECS complexes part of the DesCEND
CC (destruction via C-end degrons) pathway, which contain either KLHDC2,
CC KLHDC3, KLHDC10, APPBP2, FEM1A, FEM1B or FEM1C as substrate-recognition
CC component (By similarity). Component of the ECS(LRR1) complex with the
CC substrate recognition component LRR1 (PubMed:33590678). Component of a
CC probable ECS E3 ubiquitin-protein ligase complex containing CUL2, RBX1,
CC ELOB, ELOC and FEM1B. Part of an E3 ubiquitin-protein ligase complex
CC including ZYG11B, CUL2 and Elongin BC. Part of an E3 ubiquitin-protein
CC ligase complex including ZER1, CUL2 and Elongin BC. Interacts with
CC RBX1, RNF7, FEM1B and TIP120A/CAND1. Found in a complex composed of
CC LIMD1, VHL, EGLN1/PHD2, ELOB and CUL2. Interacts (when neddylated) with
CC ARIH1; leading to activate the E3 ligase activity of ARIH1. Interacts
CC (unneddylated form) with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and
CC DCUN1D5; these interactions promote the cullin neddylation. Component
CC of VCB (elongins BC/CUL2/VHL) complex that contains at least DCUN1D1,
CC CUL2 and VHL; this complex triggers CUL2 neddylation and consequently
CC cullin ring ligase (CRL) substrates polyubiquitylation.
CC {ECO:0000250|UniProtKB:Q13617, ECO:0000269|PubMed:33590678}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000305|PubMed:33590678}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9D4H8-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9D4H8-2; Sequence=VSP_008823;
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 (By
CC similarity). Deneddylated via its interaction with the COP9 signalosome
CC (CSN) complex. {ECO:0000250|UniProtKB:Q13617}.
CC -!- SIMILARITY: Belongs to the cullin family. {ECO:0000255|PROSITE-
CC ProRule:PRU00330}.
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DR EMBL; AK016520; BAB30283.1; -; mRNA.
DR EMBL; AK160597; BAE35903.1; -; mRNA.
DR EMBL; BC026779; AAH26779.1; -; mRNA.
DR EMBL; BC027428; AAH27428.1; -; mRNA.
DR EMBL; BC025902; AAH25902.1; -; mRNA.
DR CCDS; CCDS29032.2; -. [Q9D4H8-1]
DR RefSeq; NP_083678.2; NM_029402.3. [Q9D4H8-1]
DR RefSeq; XP_006526337.1; XM_006526274.3.
DR RefSeq; XP_006526338.1; XM_006526275.3. [Q9D4H8-1]
DR AlphaFoldDB; Q9D4H8; -.
DR SMR; Q9D4H8; -.
DR BioGRID; 214895; 41.
DR IntAct; Q9D4H8; 7.
DR MINT; Q9D4H8; -.
DR STRING; 10090.ENSMUSP00000125403; -.
DR iPTMnet; Q9D4H8; -.
DR PhosphoSitePlus; Q9D4H8; -.
DR SwissPalm; Q9D4H8; -.
DR EPD; Q9D4H8; -.
DR jPOST; Q9D4H8; -.
DR MaxQB; Q9D4H8; -.
DR PaxDb; 10090-ENSMUSP00000125403; -.
DR PeptideAtlas; Q9D4H8; -.
DR ProteomicsDB; 279209; -. [Q9D4H8-1]
DR ProteomicsDB; 279210; -. [Q9D4H8-2]
DR Pumba; Q9D4H8; -.
DR Antibodypedia; 3631; 557 antibodies from 42 providers.
DR DNASU; 71745; -.
DR Ensembl; ENSMUST00000025073.12; ENSMUSP00000025073.6; ENSMUSG00000024231.16. [Q9D4H8-2]
DR Ensembl; ENSMUST00000162301.8; ENSMUSP00000125403.2; ENSMUSG00000024231.16. [Q9D4H8-1]
DR GeneID; 71745; -.
DR KEGG; mmu:71745; -.
DR UCSC; uc008dxz.2; mouse. [Q9D4H8-2]
DR UCSC; uc008dya.2; mouse. [Q9D4H8-1]
DR AGR; MGI:1918995; -.
DR CTD; 8453; -.
DR MGI; MGI:1918995; Cul2.
DR VEuPathDB; HostDB:ENSMUSG00000024231; -.
DR eggNOG; KOG2284; Eukaryota.
DR GeneTree; ENSGT00940000154926; -.
DR HOGENOM; CLU_004747_6_1_1; -.
DR InParanoid; Q9D4H8; -.
DR OMA; VQTYQMA; -.
DR OrthoDB; 5474206at2759; -.
DR PhylomeDB; Q9D4H8; -.
DR TreeFam; TF101152; -.
DR Reactome; R-MMU-1234176; Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha.
DR Reactome; R-MMU-8951664; Neddylation.
DR Reactome; R-MMU-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 71745; 23 hits in 79 CRISPR screens.
DR ChiTaRS; Cul2; mouse.
DR PRO; PR:Q9D4H8; -.
DR Proteomes; UP000000589; Chromosome 18.
DR RNAct; Q9D4H8; Protein.
DR Bgee; ENSMUSG00000024231; Expressed in superior cervical ganglion and 269 other cell types or tissues.
DR ExpressionAtlas; Q9D4H8; baseline and differential.
DR Genevisible; Q9D4H8; MM.
DR GO; GO:0031462; C:Cul2-RING ubiquitin ligase complex; IDA:MGI.
DR GO; GO:0005730; C:nucleolus; IDA:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0019005; C:SCF ubiquitin ligase complex; IBA:GO_Central.
DR GO; GO:0030891; C:VCB complex; ISO:MGI.
DR GO; GO:0044877; F:protein-containing complex binding; ISO:MGI.
DR GO; GO:0030674; F:protein-macromolecule adaptor activity; IBA:GO_Central.
DR GO; GO:0160072; F:ubiquitin ligase complex scaffold activity; ISO:MGI.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; ISO:MGI.
DR GO; GO:0030163; P:protein catabolic process; IMP:MGI.
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; ISO:MGI.
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:SF126; 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.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Isopeptide bond; Nucleus;
KW Phosphoprotein; Reference proteome; Ubl conjugation;
KW Ubl conjugation pathway.
FT CHAIN 1..745
FT /note="Cullin-2"
FT /id="PRO_0000119791"
FT MOD_RES 393
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:23806337"
FT MOD_RES 661
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q13617"
FT CROSSLNK 689
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in NEDD8)"
FT /evidence="ECO:0000250|UniProtKB:Q13616"
FT VAR_SEQ 664..702
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:16141072"
FT /id="VSP_008823"
FT CONFLICT 612
FT /note="K -> R (in Ref. 1; BAB30283)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 745 AA; 86877 MW; 311C05CC262692E0 CRC64;
MSLKPRVVDF DETWNKLLTT IKAVVMLEYV ERATWNDRFS DIYALCVAYP EPLGERLYAE
TKIFLESHVR HLYKRVLESE EQVLVMYHRY WEEYSKGADY MDCLYRYLNT QYIKKNKLTE
ADIQYGYGGV DMNEPLMEIG ELALDMWRKL MVEPLQNILI RMLLREIKND RGGEDPNQKV
IHGVINSFVH VEQYKKKFPL KFYQGIFVSP FLTETGEYYK QEASNLLQES NCSQYMEKVL
GRLKDEEIRC RKYLHPSSYT KVIHECQQRM VADHLQFLHS ECHSIIQQER KNDMANMYVL
LRAVSSGLPH MIEELQKHIH DEGLRATSNL TQEHMPTLFV ESVLEVHGKF VQLINTVLNG
DQHFMSALDK ALTSVVNYRE PKSVCKAPEL LAKYCDNLLK KSAKGMTENE VEDKLTSFIT
VFKYIDDKDV FQKFYARMLA KRLIHGLSMS MDSEEAMINK LKQACGYEFT SKLHRMYTDM
SVSADLNNKF NNFIRNQDTV IDLGISFQIY VLQAGAWPLT QAPSSTFAIP QELEKSVQMF
ELFYSQHFSG RKLTWLHYLC TGEVKMNYLG KPYVAMVTTY QMAVLLAFNN SETVSYKELQ
DSTQMNEKEL TKTIKSLLDV KMINHDSEKE DIDAESSFSL NMSFSSKRTK FKITTSMQKD
TPQELEQTRS AVDEDRKMYL QAAIVRIMKA RKVLRHNALI QEVISQSRAR FNPSISMIKK
CIEVLIDKQY IERSQASADE YSYVA
//