Full text data of UBE2N
UBE2N
(BLU)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Ubiquitin-conjugating enzyme E2 N; 6.3.2.19 (Bendless-like ubiquitin-conjugating enzyme; Ubc13; UbcH13; Ubiquitin carrier protein N; Ubiquitin-protein ligase N)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Ubiquitin-conjugating enzyme E2 N; 6.3.2.19 (Bendless-like ubiquitin-conjugating enzyme; Ubc13; UbcH13; Ubiquitin carrier protein N; Ubiquitin-protein ligase N)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00003949
IPI00003949 Ubiquitin-conjugating enzyme E2 N ATP + ubiquitin + protein lysine = AMP + diphosphate + protein N-ubiquityllysine, non canonical ubiquitin pathway, not involved in degradation by proteasome 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 cytoplasmic n/a found at its expected molecular weight found at molecular weight
IPI00003949 Ubiquitin-conjugating enzyme E2 N ATP + ubiquitin + protein lysine = AMP + diphosphate + protein N-ubiquityllysine, non canonical ubiquitin pathway, not involved in degradation by proteasome 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 cytoplasmic n/a found at its expected molecular weight found at molecular weight
UniProt
P61088
ID UBE2N_HUMAN Reviewed; 152 AA.
AC P61088; Q16781; Q53Y81;
DT 26-APR-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 26-APR-2004, sequence version 1.
DT 22-JAN-2014, entry version 125.
DE RecName: Full=Ubiquitin-conjugating enzyme E2 N;
DE EC=6.3.2.19;
DE AltName: Full=Bendless-like ubiquitin-conjugating enzyme;
DE AltName: Full=Ubc13;
DE AltName: Full=UbcH13;
DE AltName: Full=Ubiquitin carrier protein N;
DE AltName: Full=Ubiquitin-protein ligase N;
GN Name=UBE2N; Synonyms=BLU;
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].
RX PubMed=8902611;
RA Yamaguchi T., Kim N.-S., Sekine S., Seino H., Osaka F., Yamao F.,
RA Kato S.;
RT "Cloning and expression of cDNA encoding a human ubiquitin-conjugating
RT enzyme similar to the Drosophila bendless gene product.";
RL J. Biochem. 120:494-497(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung, Placenta, 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 [4]
RP PROTEIN SEQUENCE OF 15-24; 34-68; 86-92 AND 95-102, AND MASS
RP SPECTROMETRY.
RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex;
RA Lubec G., Vishwanath V., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [5]
RP PROTEIN SEQUENCE OF 86-94, MUTAGENESIS OF LYS-92, ISGYLATION AT
RP LYS-92, AND MASS SPECTROMETRY.
RX PubMed=16122702; DOI=10.1016/j.bbrc.2005.08.038;
RA Zou W., Papov V., Malakhova O., Kim K.I., Dao C., Li J., Zhang D.-E.;
RT "ISG15 modification of ubiquitin E2 Ubc13 disrupts its ability to form
RT thioester bond with ubiquitin.";
RL Biochem. Biophys. Res. Commun. 336:61-68(2005).
RN [6]
RP FUNCTION, AND INTERACTION WITH UBE2V2.
RX PubMed=10089880; DOI=10.1016/S0092-8674(00)80575-9;
RA Hofmann R.M., Pickart C.M.;
RT "Noncanonical MMS2-encoded ubiquitin-conjugating enzyme functions in
RT assembly of novel polyubiquitin chains for DNA repair.";
RL Cell 96:645-653(1999).
RN [7]
RP FUNCTION, AND INTERACTION WITH UBE2V2.
RX PubMed=14562038; DOI=10.1038/sj.onc.1206831;
RA Bothos J., Summers M.K., Venere M., Scolnick D.M., Halazonetis T.D.;
RT "The Chfr mitotic checkpoint protein functions with Ubc13-Mms2 to form
RT Lys63-linked polyubiquitin chains.";
RL Oncogene 22:7101-7107(2003).
RN [8]
RP MUTAGENESIS OF LYS-92 AND LYS-94, AND ISGYLATION AT LYS-92.
RX PubMed=16112642; DOI=10.1016/j.bbrc.2005.08.034;
RA Takeuchi T., Yokosawa H.;
RT "ISG15 modification of Ubc13 suppresses its ubiquitin-conjugating
RT activity.";
RL Biochem. Biophys. Res. Commun. 336:9-13(2005).
RN [9]
RP INTERACTION WITH SHPRH, AND MUTAGENESIS OF CYS-87.
RX PubMed=17130289; DOI=10.1083/jcb.200606145;
RA Motegi A., Sood R., Moinova H., Markowitz S.D., Liu P.P., Myung K.;
RT "Human SHPRH suppresses genomic instability through proliferating cell
RT nuclear antigen polyubiquitination.";
RL J. Cell Biol. 175:703-708(2006).
RN [10]
RP INTERACTION WITH RNF8.
RX PubMed=16215985; DOI=10.1002/jcb.20587;
RA Plans V., Scheper J., Soler M., Loukili N., Okano Y., Thomson T.M.;
RT "The RING finger protein RNF8 recruits UBC13 for lysine 63-based self
RT polyubiquitylation.";
RL J. Cell. Biochem. 97:572-582(2006).
RN [11]
RP INTERACTION WITH SHPRH.
RX PubMed=17108083; DOI=10.1073/pnas.0608595103;
RA Unk I., Hajdu I., Fatyol K., Szakal B., Blastyak A., Bermudez V.,
RA Hurwitz J., Prakash L., Prakash S., Haracska L.;
RT "Human SHPRH is a ubiquitin ligase for Mms2-Ubc13-dependent
RT polyubiquitylation of proliferating cell nuclear antigen.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:18107-18112(2006).
RN [12]
RP MUTAGENESIS OF CYS-87.
RX PubMed=17135271; DOI=10.1074/jbc.M609503200;
RA Lamothe B., Besse A., Campos A.D., Webster W.K., Wu H., Darnay B.G.;
RT "Site-specific Lys-63-linked tumor necrosis factor receptor-associated
RT factor 6 auto-ubiquitination is a critical determinant of I kappa B
RT kinase activation.";
RL J. Biol. Chem. 282:4102-4112(2007).
RN [13]
RP INTERACTION WITH HLTF.
RX PubMed=18316726; DOI=10.1073/pnas.0800563105;
RA Unk I., Hajdu I., Fatyol K., Hurwitz J., Yoon J.-H., Prakash L.,
RA Prakash S., Haracska L.;
RT "Human HLTF functions as a ubiquitin ligase for proliferating cell
RT nuclear antigen polyubiquitination.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:3768-3773(2008).
RN [14]
RP INTERACTION WITH HLTF.
RX PubMed=18719106; DOI=10.1073/pnas.0805685105;
RA Motegi A., Liaw H.-J., Lee K.-Y., Roest H.P., Maas A., Wu X.,
RA Moinova H., Markowitz S.D., Ding H., Hoeijmakers J.H.J., Myung K.;
RT "Polyubiquitination of proliferating cell nuclear antigen by HLTF and
RT SHPRH prevents genomic instability from stalled replication forks.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:12411-12416(2008).
RN [15]
RP INTERACTION WITH RNF168.
RX PubMed=19203578; DOI=10.1016/j.cell.2008.12.042;
RA Stewart G.S., Panier S., Townsend K., Al-Hakim A.K., Kolas N.K.,
RA Miller E.S., Nakada S., Ylanko J., Olivarius S., Mendez M.,
RA Oldreive C., Wildenhain J., Tagliaferro A., Pelletier L.,
RA Taubenheim N., Durandy A., Byrd P.J., Stankovic T., Taylor A.M.R.,
RA Durocher D.;
RT "The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling
RT cascade at sites of DNA damage.";
RL Cell 136:420-434(2009).
RN [16]
RP FUNCTION IN UBIQUITINATION OF JKAMP.
RX PubMed=19269966; DOI=10.1074/jbc.M808222200;
RA Tcherpakov M., Delaunay A., Toth J., Kadoya T., Petroski M.D.,
RA Ronai Z.A.;
RT "Regulation of endoplasmic reticulum-associated degradation by RNF5-
RT dependent ubiquitination of JNK-associated membrane protein (JAMP).";
RL J. Biol. Chem. 284:12099-12109(2009).
RN [17]
RP INTERACTION WITH ARIH2, AND SUBCELLULAR LOCATION.
RX PubMed=19340006; DOI=10.1038/leu.2009.57;
RA Marteijn J.A., van der Meer L.T., Smit J.J., Noordermeer S.M.,
RA Wissink W., Jansen P., Swarts H.G., Hibbert R.G., de Witte T.,
RA Sixma T.K., Jansen J.H., van der Reijden B.A.;
RT "The ubiquitin ligase Triad1 inhibits myelopoiesis through UbcH7 and
RT Ubc13 interacting domains.";
RL Leukemia 23:1480-1489(2009).
RN [18]
RP INTERACTION WITH RNF11.
RX PubMed=18615712; DOI=10.1002/prot.22120;
RA Scheper J., Oliva B., Villa-Freixa J., Thomson T.M.;
RT "Analysis of electrostatic contributions to the selectivity of
RT interactions between RING-finger domains and ubiquitin-conjugating
RT enzymes.";
RL Proteins 74:92-103(2009).
RN [19]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-82, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., 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 [20]
RP FUNCTION.
RX PubMed=20061386; DOI=10.1074/jbc.M109.089003;
RA David Y., Ziv T., Admon A., Navon A.;
RT "The E2 ubiquitin-conjugating enzymes direct polyubiquitination to
RT preferred lysines.";
RL J. Biol. Chem. 285:8595-8604(2010).
RN [21]
RP ENZYME REGULATION, AND INTERACTION WITH OTUB1.
RX PubMed=20725033; DOI=10.1038/nature09297;
RA Nakada S., Tai I., Panier S., Al-Hakim A., Iemura S., Juang Y.C.,
RA O'Donnell L., Kumakubo A., Munro M., Sicheri F., Gingras A.C.,
RA Natsume T., Suda T., Durocher D.;
RT "Non-canonical inhibition of DNA damage-dependent ubiquitination by
RT OTUB1.";
RL Nature 466:941-946(2010).
RN [22]
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 [23]
RP FUNCTION.
RX PubMed=21512573; DOI=10.1038/nature09976;
RA Pertel T., Hausmann S., Morger D., Zueger S., Guerra J., Lascano J.,
RA Reinhard C., Santoni F.A., Uchil P.D., Chatel L., Bisiaux A.,
RA Albert M.L., Strambio-De-Castillia C., Mothes W., Pizzato M.,
RA Gruetter M.G., Luban J.;
RT "TRIM5 is an innate immune sensor for the retrovirus capsid lattice.";
RL Nature 472:361-365(2011).
RN [24]
RP IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=21659603; DOI=10.1126/science.1203430;
RA Cotta-Ramusino C., McDonald E.R. III, Hurov K., Sowa M.E.,
RA Harper J.W., Elledge S.J.;
RT "A DNA damage response screen identifies RHINO, a 9-1-1 and TopBP1
RT interacting protein required for ATR signaling.";
RL Science 332:1313-1317(2011).
RN [25]
RP ISGYLATION, AND DISULFIDE BOND.
RX PubMed=22693631; DOI=10.1371/journal.pone.0038294;
RA Bade V.N., Nickels J., Keusekotten K., Praefcke G.J.;
RT "Covalent protein modification with ISG15 via a conserved cysteine in
RT the hinge region.";
RL PLoS ONE 7:E38294-E38294(2012).
RN [26]
RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) IN COMPLEX WITH UBE2V2.
RX PubMed=11473255; DOI=10.1038/90373;
RA Moraes T.F., Edwards R.A., McKenna S., Pastushok L., Xiao W.,
RA Glover J.N.M., Ellison M.J.;
RT "Crystal structure of the human ubiquitin conjugating enzyme complex,
RT hMms2-hUbc13.";
RL Nat. Struct. Biol. 8:669-673(2001).
RN [27]
RP X-RAY CRYSTALLOGRAPHY (2.90 ANGSTROMS) OF 2-152 IN COMPLEX WITH STUB1
RP AND UBE2V1.
RX PubMed=16307917; DOI=10.1016/j.molcel.2005.09.023;
RA Zhang M., Windheim M., Roe S.M., Peggie M., Cohen P., Prodromou C.,
RA Pearl L.H.;
RT "Chaperoned ubiquitylation -- crystal structures of the CHIP U box E3
RT ubiquitin ligase and a CHIP-Ubc13-Uev1a complex.";
RL Mol. Cell 20:525-538(2005).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (4.8 ANGSTROMS) OF 1-150 IN COMPLEX WITH RNF8
RP AND UBE2V2.
RX PubMed=22589545; DOI=10.1074/jbc.M112.359653;
RA Campbell S.J., Edwards R.A., Leung C.C., Neculai D., Hodge C.D.,
RA Dhe-Paganon S., Glover J.N.;
RT "Molecular insights into the function of RING Finger (RNF)-containing
RT proteins hRNF8 and hRNF168 in Ubc13/Mms2-dependent ubiquitylation.";
RL J. Biol. Chem. 287:23900-23910(2012).
RN [29]
RP X-RAY CRYSTALLOGRAPHY (3.3 ANGSTROMS) OF 25-271 IN COMPLEX WITH UBE2V2
RP AND OTUB1, ENZYME REGULATION, AND INTERACTION WITH OTUB1.
RX PubMed=22325355; DOI=10.1016/j.molcel.2012.01.011;
RA Juang Y.C., Landry M.C., Sanches M., Vittal V., Leung C.C.,
RA Ceccarelli D.F., Mateo A.R., Pruneda J.N., Mao D.Y., Szilard R.K.,
RA Orlicky S., Munro M., Brzovic P.S., Klevit R.E., Sicheri F.,
RA Durocher D.;
RT "OTUB1 co-opts Lys48-linked ubiquitin recognition to suppress E2
RT enzyme function.";
RL Mol. Cell 45:384-397(2012).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (3.11 ANGSTROMS) IN COMPLEX WITH OUTB1 AND
RP UBIQUITIN, ENZYME REGULATION, AND INTERACTION WITH OTUB1.
RX PubMed=22367539; DOI=10.1038/nature10911;
RA Wiener R., Zhang X., Wang T., Wolberger C.;
RT "The mechanism of OTUB1-mediated inhibition of ubiquitination.";
RL Nature 483:618-622(2012).
CC -!- FUNCTION: The UBE2V1-UBE2N and UBE2V2-UBE2N heterodimers catalyze
CC the synthesis of non-canonical 'Lys-63'-linked polyubiquitin
CC chains. This type of polyubiquitination does not lead to protein
CC degradation by the proteasome. Mediates transcriptional activation
CC of target genes. Plays a role in the control of progress through
CC the cell cycle and differentiation. Plays a role in the error-free
CC DNA repair pathway and contributes to the survival of cells after
CC DNA damage. Acts together with the E3 ligases, HLTF and SHPRH, in
CC the 'Lys-63'-linked poly-ubiquitination of PCNA upon genotoxic
CC stress, which is required for DNA repair. Appears to act together
CC with E3 ligase RNF5 in the 'Lys-63'-linked polyubiquitination of
CC JKAMP thereby regulating JKAMP function by decreasing its
CC association with components of the proteasome and ERAD. Promotes
CC TRIM5 capsid-specific restriction activity and the UBE2V1-UBE2N
CC heterodimer acts in concert with TRIM5 to generate 'Lys-63'-linked
CC polyubiquitin chains which activate the MAP3K7/TAK1 complex which
CC in turn results in the induction and expression of NF-kappa-B and
CC MAPK-responsive inflammatory genes (By similarity).
CC -!- CATALYTIC ACTIVITY: ATP + ubiquitin + protein lysine = AMP +
CC diphosphate + protein N-ubiquityllysine.
CC -!- ENZYME REGULATION: Activity is inhibited by binding to OTUB1,
CC which prevents 'Lys-63'-linked polyubiquitination.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Heterodimer with UBE2V2. Interacts (UBE2V2-UBE2N
CC heterodimer) with the E3 ligase STUB1 (via the U-box domain); the
CC complex has a specific 'Lys-63'-linked polyubiquitination
CC activity. Interacts with RNF8 and RNF168. Interacts with RNF11.
CC Interacts with the E3 ligases, HLTF and SHPRH; the interactions
CC promote the 'Lys-63'-linked polyubiquitination of PCNA upon
CC genotoxic stress and lead to DNA repair. Interacts with ARIH2 (via
CC RING-type 2). Interacts with OTUB1; leading to inhibit E2-
CC conjugating activity.
CC -!- INTERACTION:
CC Q9Y3C5:RNF11; NbExp=4; IntAct=EBI-1052908, EBI-396669;
CC Q8IYW5:RNF168; NbExp=2; IntAct=EBI-1052908, EBI-914207;
CC Q9UNE7:STUB1; NbExp=3; IntAct=EBI-1052908, EBI-357085;
CC Q9WUD1:Stub1 (xeno); NbExp=2; IntAct=EBI-1052908, EBI-773027;
CC Q9Y4K3:TRAF6; NbExp=3; IntAct=EBI-1052908, EBI-359276;
CC Q13404:UBE2V1; NbExp=9; IntAct=EBI-1052908, EBI-1050671;
CC Q15819:UBE2V2; NbExp=3; IntAct=EBI-1052908, EBI-714329;
CC P98170:XIAP; NbExp=2; IntAct=EBI-1052908, EBI-517127;
CC Q8ND25:ZNRF1; NbExp=3; IntAct=EBI-1052908, EBI-2129250;
CC -!- SUBCELLULAR LOCATION: Nucleus. Cytoplasm.
CC -!- PTM: Conjugation to ISG15 impairs formation of the thioester bond
CC with ubiquitin but not interaction with UBE2V2.
CC -!- SIMILARITY: Belongs to the ubiquitin-conjugating enzyme family.
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DR EMBL; D83004; BAA11675.1; -; mRNA.
DR EMBL; BT006873; AAP35519.1; -; mRNA.
DR EMBL; BC000396; AAH00396.1; -; mRNA.
DR EMBL; BC003365; AAH03365.1; -; mRNA.
DR EMBL; BC108704; AAI08705.1; -; mRNA.
DR PIR; JC4894; JC4894.
DR RefSeq; NP_003339.1; NM_003348.3.
DR UniGene; Hs.524630; -.
DR PDB; 1J7D; X-ray; 1.85 A; B=1-152.
DR PDB; 2C2V; X-ray; 2.90 A; B/E/H/K=2-152.
DR PDB; 3HCT; X-ray; 2.10 A; B=1-152.
DR PDB; 3HCU; X-ray; 2.60 A; B/D=1-152.
DR PDB; 3VON; X-ray; 3.15 A; C/E/G/J/L/N/Q/S/U/X/Z/b/e/g/i/l/n/p=3-150.
DR PDB; 3W31; X-ray; 2.96 A; B=1-152.
DR PDB; 4DHI; X-ray; 1.80 A; D=1-152.
DR PDB; 4DHJ; X-ray; 2.35 A; C/G/K/N=1-152.
DR PDB; 4DHZ; X-ray; 3.11 A; F=1-152.
DR PDB; 4EPO; X-ray; 4.80 A; B/F/J=1-150.
DR PDB; 4IP3; X-ray; 2.30 A; B=1-152.
DR PDBsum; 1J7D; -.
DR PDBsum; 2C2V; -.
DR PDBsum; 3HCT; -.
DR PDBsum; 3HCU; -.
DR PDBsum; 3VON; -.
DR PDBsum; 3W31; -.
DR PDBsum; 4DHI; -.
DR PDBsum; 4DHJ; -.
DR PDBsum; 4DHZ; -.
DR PDBsum; 4EPO; -.
DR PDBsum; 4IP3; -.
DR ProteinModelPortal; P61088; -.
DR SMR; P61088; 3-152.
DR DIP; DIP-29829N; -.
DR IntAct; P61088; 57.
DR MINT; MINT-5001139; -.
DR STRING; 9606.ENSP00000316176; -.
DR BindingDB; P61088; -.
DR ChEMBL; CHEMBL6089; -.
DR PhosphoSite; P61088; -.
DR DMDM; 46577660; -.
DR OGP; Q16781; -.
DR REPRODUCTION-2DPAGE; IPI00003949; -.
DR PaxDb; P61088; -.
DR PeptideAtlas; P61088; -.
DR PRIDE; P61088; -.
DR DNASU; 7334; -.
DR Ensembl; ENST00000318066; ENSP00000316176; ENSG00000177889.
DR GeneID; 7334; -.
DR KEGG; hsa:7334; -.
DR UCSC; uc001tcp.3; human.
DR CTD; 7334; -.
DR GeneCards; GC12M093735; -.
DR HGNC; HGNC:12492; UBE2N.
DR HPA; HPA003962; -.
DR MIM; 603679; gene.
DR neXtProt; NX_P61088; -.
DR PharmGKB; PA37141; -.
DR eggNOG; COG5078; -.
DR HOGENOM; HOG000233455; -.
DR HOVERGEN; HBG063308; -.
DR InParanoid; P61088; -.
DR KO; K10580; -.
DR OMA; DVAKHYK; -.
DR OrthoDB; EOG7XWPQB; -.
DR PhylomeDB; P61088; -.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P61088; -.
DR UniPathway; UPA00143; -.
DR ChiTaRS; UBE2N; human.
DR EvolutionaryTrace; P61088; -.
DR GeneWiki; UBE2N; -.
DR GenomeRNAi; 7334; -.
DR NextBio; 28704; -.
DR PRO; PR:P61088; -.
DR ArrayExpress; P61088; -.
DR Bgee; P61088; -.
DR CleanEx; HS_UBE2N; -.
DR Genevestigator; P61088; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0031372; C:UBC13-MMS2 complex; IDA:HGNC.
DR GO; GO:0035370; C:UBC13-UEV1A complex; IDA:UniProtKB.
DR GO; GO:0000151; C:ubiquitin ligase complex; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0043130; F:ubiquitin binding; IDA:HGNC.
DR GO; GO:0004842; F:ubiquitin-protein ligase activity; IDA:UniProtKB.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0000729; P:DNA double-strand break processing; IMP:HGNC.
DR GO; GO:0000724; P:double-strand break repair via homologous recombination; IMP:HGNC.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0016574; P:histone ubiquitination; IMP:HGNC.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0070423; P:nucleotide-binding oligomerization domain containing signaling pathway; TAS:Reactome.
DR GO; GO:0045739; P:positive regulation of DNA repair; IMP:HGNC.
DR GO; GO:0031058; P:positive regulation of histone modification; IMP:HGNC.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; IMP:HGNC.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IMP:UniProtKB.
DR GO; GO:0051443; P:positive regulation of ubiquitin-protein ligase activity; IMP:HGNC.
DR GO; GO:0006301; P:postreplication repair; IMP:HGNC.
DR GO; GO:0070534; P:protein K63-linked ubiquitination; IDA:UniProtKB.
DR GO; GO:0006508; P:proteolysis; TAS:ProtInc.
DR GO; GO:0033182; P:regulation of histone ubiquitination; IMP:HGNC.
DR GO; GO:0050852; P:T cell receptor signaling pathway; IMP:UniProtKB.
DR GO; GO:0034166; P:toll-like receptor 10 signaling pathway; TAS:Reactome.
DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; TAS:Reactome.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR GO; GO:0034146; P:toll-like receptor 5 signaling pathway; TAS:Reactome.
DR GO; GO:0034162; P:toll-like receptor 9 signaling pathway; TAS:Reactome.
DR GO; GO:0038123; P:toll-like receptor TLR1:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0038124; P:toll-like receptor TLR6:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IEA:Ensembl.
DR Gene3D; 3.10.110.10; -; 1.
DR InterPro; IPR000608; UBQ-conjugat_E2.
DR InterPro; IPR023313; UBQ-conjugating_AS.
DR InterPro; IPR016135; UBQ-conjugating_enzyme/RWD.
DR Pfam; PF00179; UQ_con; 1.
DR SUPFAM; SSF54495; SSF54495; 1.
DR PROSITE; PS00183; UBIQUITIN_CONJUGAT_1; 1.
DR PROSITE; PS50127; UBIQUITIN_CONJUGAT_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; ATP-binding; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Disulfide bond; DNA damage; DNA repair;
KW Isopeptide bond; Ligase; Nucleotide-binding; Nucleus;
KW Reference proteome; Ubl conjugation; Ubl conjugation pathway.
FT CHAIN 1 152 Ubiquitin-conjugating enzyme E2 N.
FT /FTId=PRO_0000082502.
FT ACT_SITE 87 87 Glycyl thioester intermediate.
FT MOD_RES 82 82 N6-acetyllysine.
FT DISULFID 87 87 Interchain (with C-78 in ISG15).
FT CROSSLNK 92 92 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ISG15).
FT MUTAGEN 87 87 C->A: Loss of polyubiquitination of PCNA.
FT Impairs interaction with SHPRH.
FT MUTAGEN 92 92 K->R: No ISGylation.
FT MUTAGEN 94 94 K->R: No effect on ISGylation.
FT HELIX 6 17
FT STRAND 23 27
FT STRAND 34 40
FT TURN 46 49
FT STRAND 51 57
FT TURN 60 63
FT STRAND 68 73
FT HELIX 89 91
FT TURN 92 94
FT HELIX 101 113
FT HELIX 124 131
FT HELIX 133 147
FT STRAND 148 150
SQ SEQUENCE 152 AA; 17138 MW; FACD84D883D77407 CRC64;
MAGLPRRIIK ETQRLLAEPV PGIKAEPDES NARYFHVVIA GPQDSPFEGG TFKLELFLPE
EYPMAAPKVR FMTKIYHPNV DKLGRICLDI LKDKWSPALQ IRTVLLSIQA LLSAPNPDDP
LANDVAEQWK TNEAQAIETA RAWTRLYAMN NI
//
ID UBE2N_HUMAN Reviewed; 152 AA.
AC P61088; Q16781; Q53Y81;
DT 26-APR-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 26-APR-2004, sequence version 1.
DT 22-JAN-2014, entry version 125.
DE RecName: Full=Ubiquitin-conjugating enzyme E2 N;
DE EC=6.3.2.19;
DE AltName: Full=Bendless-like ubiquitin-conjugating enzyme;
DE AltName: Full=Ubc13;
DE AltName: Full=UbcH13;
DE AltName: Full=Ubiquitin carrier protein N;
DE AltName: Full=Ubiquitin-protein ligase N;
GN Name=UBE2N; Synonyms=BLU;
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].
RX PubMed=8902611;
RA Yamaguchi T., Kim N.-S., Sekine S., Seino H., Osaka F., Yamao F.,
RA Kato S.;
RT "Cloning and expression of cDNA encoding a human ubiquitin-conjugating
RT enzyme similar to the Drosophila bendless gene product.";
RL J. Biochem. 120:494-497(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung, Placenta, 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 [4]
RP PROTEIN SEQUENCE OF 15-24; 34-68; 86-92 AND 95-102, AND MASS
RP SPECTROMETRY.
RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex;
RA Lubec G., Vishwanath V., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [5]
RP PROTEIN SEQUENCE OF 86-94, MUTAGENESIS OF LYS-92, ISGYLATION AT
RP LYS-92, AND MASS SPECTROMETRY.
RX PubMed=16122702; DOI=10.1016/j.bbrc.2005.08.038;
RA Zou W., Papov V., Malakhova O., Kim K.I., Dao C., Li J., Zhang D.-E.;
RT "ISG15 modification of ubiquitin E2 Ubc13 disrupts its ability to form
RT thioester bond with ubiquitin.";
RL Biochem. Biophys. Res. Commun. 336:61-68(2005).
RN [6]
RP FUNCTION, AND INTERACTION WITH UBE2V2.
RX PubMed=10089880; DOI=10.1016/S0092-8674(00)80575-9;
RA Hofmann R.M., Pickart C.M.;
RT "Noncanonical MMS2-encoded ubiquitin-conjugating enzyme functions in
RT assembly of novel polyubiquitin chains for DNA repair.";
RL Cell 96:645-653(1999).
RN [7]
RP FUNCTION, AND INTERACTION WITH UBE2V2.
RX PubMed=14562038; DOI=10.1038/sj.onc.1206831;
RA Bothos J., Summers M.K., Venere M., Scolnick D.M., Halazonetis T.D.;
RT "The Chfr mitotic checkpoint protein functions with Ubc13-Mms2 to form
RT Lys63-linked polyubiquitin chains.";
RL Oncogene 22:7101-7107(2003).
RN [8]
RP MUTAGENESIS OF LYS-92 AND LYS-94, AND ISGYLATION AT LYS-92.
RX PubMed=16112642; DOI=10.1016/j.bbrc.2005.08.034;
RA Takeuchi T., Yokosawa H.;
RT "ISG15 modification of Ubc13 suppresses its ubiquitin-conjugating
RT activity.";
RL Biochem. Biophys. Res. Commun. 336:9-13(2005).
RN [9]
RP INTERACTION WITH SHPRH, AND MUTAGENESIS OF CYS-87.
RX PubMed=17130289; DOI=10.1083/jcb.200606145;
RA Motegi A., Sood R., Moinova H., Markowitz S.D., Liu P.P., Myung K.;
RT "Human SHPRH suppresses genomic instability through proliferating cell
RT nuclear antigen polyubiquitination.";
RL J. Cell Biol. 175:703-708(2006).
RN [10]
RP INTERACTION WITH RNF8.
RX PubMed=16215985; DOI=10.1002/jcb.20587;
RA Plans V., Scheper J., Soler M., Loukili N., Okano Y., Thomson T.M.;
RT "The RING finger protein RNF8 recruits UBC13 for lysine 63-based self
RT polyubiquitylation.";
RL J. Cell. Biochem. 97:572-582(2006).
RN [11]
RP INTERACTION WITH SHPRH.
RX PubMed=17108083; DOI=10.1073/pnas.0608595103;
RA Unk I., Hajdu I., Fatyol K., Szakal B., Blastyak A., Bermudez V.,
RA Hurwitz J., Prakash L., Prakash S., Haracska L.;
RT "Human SHPRH is a ubiquitin ligase for Mms2-Ubc13-dependent
RT polyubiquitylation of proliferating cell nuclear antigen.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:18107-18112(2006).
RN [12]
RP MUTAGENESIS OF CYS-87.
RX PubMed=17135271; DOI=10.1074/jbc.M609503200;
RA Lamothe B., Besse A., Campos A.D., Webster W.K., Wu H., Darnay B.G.;
RT "Site-specific Lys-63-linked tumor necrosis factor receptor-associated
RT factor 6 auto-ubiquitination is a critical determinant of I kappa B
RT kinase activation.";
RL J. Biol. Chem. 282:4102-4112(2007).
RN [13]
RP INTERACTION WITH HLTF.
RX PubMed=18316726; DOI=10.1073/pnas.0800563105;
RA Unk I., Hajdu I., Fatyol K., Hurwitz J., Yoon J.-H., Prakash L.,
RA Prakash S., Haracska L.;
RT "Human HLTF functions as a ubiquitin ligase for proliferating cell
RT nuclear antigen polyubiquitination.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:3768-3773(2008).
RN [14]
RP INTERACTION WITH HLTF.
RX PubMed=18719106; DOI=10.1073/pnas.0805685105;
RA Motegi A., Liaw H.-J., Lee K.-Y., Roest H.P., Maas A., Wu X.,
RA Moinova H., Markowitz S.D., Ding H., Hoeijmakers J.H.J., Myung K.;
RT "Polyubiquitination of proliferating cell nuclear antigen by HLTF and
RT SHPRH prevents genomic instability from stalled replication forks.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:12411-12416(2008).
RN [15]
RP INTERACTION WITH RNF168.
RX PubMed=19203578; DOI=10.1016/j.cell.2008.12.042;
RA Stewart G.S., Panier S., Townsend K., Al-Hakim A.K., Kolas N.K.,
RA Miller E.S., Nakada S., Ylanko J., Olivarius S., Mendez M.,
RA Oldreive C., Wildenhain J., Tagliaferro A., Pelletier L.,
RA Taubenheim N., Durandy A., Byrd P.J., Stankovic T., Taylor A.M.R.,
RA Durocher D.;
RT "The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling
RT cascade at sites of DNA damage.";
RL Cell 136:420-434(2009).
RN [16]
RP FUNCTION IN UBIQUITINATION OF JKAMP.
RX PubMed=19269966; DOI=10.1074/jbc.M808222200;
RA Tcherpakov M., Delaunay A., Toth J., Kadoya T., Petroski M.D.,
RA Ronai Z.A.;
RT "Regulation of endoplasmic reticulum-associated degradation by RNF5-
RT dependent ubiquitination of JNK-associated membrane protein (JAMP).";
RL J. Biol. Chem. 284:12099-12109(2009).
RN [17]
RP INTERACTION WITH ARIH2, AND SUBCELLULAR LOCATION.
RX PubMed=19340006; DOI=10.1038/leu.2009.57;
RA Marteijn J.A., van der Meer L.T., Smit J.J., Noordermeer S.M.,
RA Wissink W., Jansen P., Swarts H.G., Hibbert R.G., de Witte T.,
RA Sixma T.K., Jansen J.H., van der Reijden B.A.;
RT "The ubiquitin ligase Triad1 inhibits myelopoiesis through UbcH7 and
RT Ubc13 interacting domains.";
RL Leukemia 23:1480-1489(2009).
RN [18]
RP INTERACTION WITH RNF11.
RX PubMed=18615712; DOI=10.1002/prot.22120;
RA Scheper J., Oliva B., Villa-Freixa J., Thomson T.M.;
RT "Analysis of electrostatic contributions to the selectivity of
RT interactions between RING-finger domains and ubiquitin-conjugating
RT enzymes.";
RL Proteins 74:92-103(2009).
RN [19]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-82, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., 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 [20]
RP FUNCTION.
RX PubMed=20061386; DOI=10.1074/jbc.M109.089003;
RA David Y., Ziv T., Admon A., Navon A.;
RT "The E2 ubiquitin-conjugating enzymes direct polyubiquitination to
RT preferred lysines.";
RL J. Biol. Chem. 285:8595-8604(2010).
RN [21]
RP ENZYME REGULATION, AND INTERACTION WITH OTUB1.
RX PubMed=20725033; DOI=10.1038/nature09297;
RA Nakada S., Tai I., Panier S., Al-Hakim A., Iemura S., Juang Y.C.,
RA O'Donnell L., Kumakubo A., Munro M., Sicheri F., Gingras A.C.,
RA Natsume T., Suda T., Durocher D.;
RT "Non-canonical inhibition of DNA damage-dependent ubiquitination by
RT OTUB1.";
RL Nature 466:941-946(2010).
RN [22]
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 [23]
RP FUNCTION.
RX PubMed=21512573; DOI=10.1038/nature09976;
RA Pertel T., Hausmann S., Morger D., Zueger S., Guerra J., Lascano J.,
RA Reinhard C., Santoni F.A., Uchil P.D., Chatel L., Bisiaux A.,
RA Albert M.L., Strambio-De-Castillia C., Mothes W., Pizzato M.,
RA Gruetter M.G., Luban J.;
RT "TRIM5 is an innate immune sensor for the retrovirus capsid lattice.";
RL Nature 472:361-365(2011).
RN [24]
RP IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=21659603; DOI=10.1126/science.1203430;
RA Cotta-Ramusino C., McDonald E.R. III, Hurov K., Sowa M.E.,
RA Harper J.W., Elledge S.J.;
RT "A DNA damage response screen identifies RHINO, a 9-1-1 and TopBP1
RT interacting protein required for ATR signaling.";
RL Science 332:1313-1317(2011).
RN [25]
RP ISGYLATION, AND DISULFIDE BOND.
RX PubMed=22693631; DOI=10.1371/journal.pone.0038294;
RA Bade V.N., Nickels J., Keusekotten K., Praefcke G.J.;
RT "Covalent protein modification with ISG15 via a conserved cysteine in
RT the hinge region.";
RL PLoS ONE 7:E38294-E38294(2012).
RN [26]
RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) IN COMPLEX WITH UBE2V2.
RX PubMed=11473255; DOI=10.1038/90373;
RA Moraes T.F., Edwards R.A., McKenna S., Pastushok L., Xiao W.,
RA Glover J.N.M., Ellison M.J.;
RT "Crystal structure of the human ubiquitin conjugating enzyme complex,
RT hMms2-hUbc13.";
RL Nat. Struct. Biol. 8:669-673(2001).
RN [27]
RP X-RAY CRYSTALLOGRAPHY (2.90 ANGSTROMS) OF 2-152 IN COMPLEX WITH STUB1
RP AND UBE2V1.
RX PubMed=16307917; DOI=10.1016/j.molcel.2005.09.023;
RA Zhang M., Windheim M., Roe S.M., Peggie M., Cohen P., Prodromou C.,
RA Pearl L.H.;
RT "Chaperoned ubiquitylation -- crystal structures of the CHIP U box E3
RT ubiquitin ligase and a CHIP-Ubc13-Uev1a complex.";
RL Mol. Cell 20:525-538(2005).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (4.8 ANGSTROMS) OF 1-150 IN COMPLEX WITH RNF8
RP AND UBE2V2.
RX PubMed=22589545; DOI=10.1074/jbc.M112.359653;
RA Campbell S.J., Edwards R.A., Leung C.C., Neculai D., Hodge C.D.,
RA Dhe-Paganon S., Glover J.N.;
RT "Molecular insights into the function of RING Finger (RNF)-containing
RT proteins hRNF8 and hRNF168 in Ubc13/Mms2-dependent ubiquitylation.";
RL J. Biol. Chem. 287:23900-23910(2012).
RN [29]
RP X-RAY CRYSTALLOGRAPHY (3.3 ANGSTROMS) OF 25-271 IN COMPLEX WITH UBE2V2
RP AND OTUB1, ENZYME REGULATION, AND INTERACTION WITH OTUB1.
RX PubMed=22325355; DOI=10.1016/j.molcel.2012.01.011;
RA Juang Y.C., Landry M.C., Sanches M., Vittal V., Leung C.C.,
RA Ceccarelli D.F., Mateo A.R., Pruneda J.N., Mao D.Y., Szilard R.K.,
RA Orlicky S., Munro M., Brzovic P.S., Klevit R.E., Sicheri F.,
RA Durocher D.;
RT "OTUB1 co-opts Lys48-linked ubiquitin recognition to suppress E2
RT enzyme function.";
RL Mol. Cell 45:384-397(2012).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (3.11 ANGSTROMS) IN COMPLEX WITH OUTB1 AND
RP UBIQUITIN, ENZYME REGULATION, AND INTERACTION WITH OTUB1.
RX PubMed=22367539; DOI=10.1038/nature10911;
RA Wiener R., Zhang X., Wang T., Wolberger C.;
RT "The mechanism of OTUB1-mediated inhibition of ubiquitination.";
RL Nature 483:618-622(2012).
CC -!- FUNCTION: The UBE2V1-UBE2N and UBE2V2-UBE2N heterodimers catalyze
CC the synthesis of non-canonical 'Lys-63'-linked polyubiquitin
CC chains. This type of polyubiquitination does not lead to protein
CC degradation by the proteasome. Mediates transcriptional activation
CC of target genes. Plays a role in the control of progress through
CC the cell cycle and differentiation. Plays a role in the error-free
CC DNA repair pathway and contributes to the survival of cells after
CC DNA damage. Acts together with the E3 ligases, HLTF and SHPRH, in
CC the 'Lys-63'-linked poly-ubiquitination of PCNA upon genotoxic
CC stress, which is required for DNA repair. Appears to act together
CC with E3 ligase RNF5 in the 'Lys-63'-linked polyubiquitination of
CC JKAMP thereby regulating JKAMP function by decreasing its
CC association with components of the proteasome and ERAD. Promotes
CC TRIM5 capsid-specific restriction activity and the UBE2V1-UBE2N
CC heterodimer acts in concert with TRIM5 to generate 'Lys-63'-linked
CC polyubiquitin chains which activate the MAP3K7/TAK1 complex which
CC in turn results in the induction and expression of NF-kappa-B and
CC MAPK-responsive inflammatory genes (By similarity).
CC -!- CATALYTIC ACTIVITY: ATP + ubiquitin + protein lysine = AMP +
CC diphosphate + protein N-ubiquityllysine.
CC -!- ENZYME REGULATION: Activity is inhibited by binding to OTUB1,
CC which prevents 'Lys-63'-linked polyubiquitination.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Heterodimer with UBE2V2. Interacts (UBE2V2-UBE2N
CC heterodimer) with the E3 ligase STUB1 (via the U-box domain); the
CC complex has a specific 'Lys-63'-linked polyubiquitination
CC activity. Interacts with RNF8 and RNF168. Interacts with RNF11.
CC Interacts with the E3 ligases, HLTF and SHPRH; the interactions
CC promote the 'Lys-63'-linked polyubiquitination of PCNA upon
CC genotoxic stress and lead to DNA repair. Interacts with ARIH2 (via
CC RING-type 2). Interacts with OTUB1; leading to inhibit E2-
CC conjugating activity.
CC -!- INTERACTION:
CC Q9Y3C5:RNF11; NbExp=4; IntAct=EBI-1052908, EBI-396669;
CC Q8IYW5:RNF168; NbExp=2; IntAct=EBI-1052908, EBI-914207;
CC Q9UNE7:STUB1; NbExp=3; IntAct=EBI-1052908, EBI-357085;
CC Q9WUD1:Stub1 (xeno); NbExp=2; IntAct=EBI-1052908, EBI-773027;
CC Q9Y4K3:TRAF6; NbExp=3; IntAct=EBI-1052908, EBI-359276;
CC Q13404:UBE2V1; NbExp=9; IntAct=EBI-1052908, EBI-1050671;
CC Q15819:UBE2V2; NbExp=3; IntAct=EBI-1052908, EBI-714329;
CC P98170:XIAP; NbExp=2; IntAct=EBI-1052908, EBI-517127;
CC Q8ND25:ZNRF1; NbExp=3; IntAct=EBI-1052908, EBI-2129250;
CC -!- SUBCELLULAR LOCATION: Nucleus. Cytoplasm.
CC -!- PTM: Conjugation to ISG15 impairs formation of the thioester bond
CC with ubiquitin but not interaction with UBE2V2.
CC -!- SIMILARITY: Belongs to the ubiquitin-conjugating enzyme family.
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DR EMBL; D83004; BAA11675.1; -; mRNA.
DR EMBL; BT006873; AAP35519.1; -; mRNA.
DR EMBL; BC000396; AAH00396.1; -; mRNA.
DR EMBL; BC003365; AAH03365.1; -; mRNA.
DR EMBL; BC108704; AAI08705.1; -; mRNA.
DR PIR; JC4894; JC4894.
DR RefSeq; NP_003339.1; NM_003348.3.
DR UniGene; Hs.524630; -.
DR PDB; 1J7D; X-ray; 1.85 A; B=1-152.
DR PDB; 2C2V; X-ray; 2.90 A; B/E/H/K=2-152.
DR PDB; 3HCT; X-ray; 2.10 A; B=1-152.
DR PDB; 3HCU; X-ray; 2.60 A; B/D=1-152.
DR PDB; 3VON; X-ray; 3.15 A; C/E/G/J/L/N/Q/S/U/X/Z/b/e/g/i/l/n/p=3-150.
DR PDB; 3W31; X-ray; 2.96 A; B=1-152.
DR PDB; 4DHI; X-ray; 1.80 A; D=1-152.
DR PDB; 4DHJ; X-ray; 2.35 A; C/G/K/N=1-152.
DR PDB; 4DHZ; X-ray; 3.11 A; F=1-152.
DR PDB; 4EPO; X-ray; 4.80 A; B/F/J=1-150.
DR PDB; 4IP3; X-ray; 2.30 A; B=1-152.
DR PDBsum; 1J7D; -.
DR PDBsum; 2C2V; -.
DR PDBsum; 3HCT; -.
DR PDBsum; 3HCU; -.
DR PDBsum; 3VON; -.
DR PDBsum; 3W31; -.
DR PDBsum; 4DHI; -.
DR PDBsum; 4DHJ; -.
DR PDBsum; 4DHZ; -.
DR PDBsum; 4EPO; -.
DR PDBsum; 4IP3; -.
DR ProteinModelPortal; P61088; -.
DR SMR; P61088; 3-152.
DR DIP; DIP-29829N; -.
DR IntAct; P61088; 57.
DR MINT; MINT-5001139; -.
DR STRING; 9606.ENSP00000316176; -.
DR BindingDB; P61088; -.
DR ChEMBL; CHEMBL6089; -.
DR PhosphoSite; P61088; -.
DR DMDM; 46577660; -.
DR OGP; Q16781; -.
DR REPRODUCTION-2DPAGE; IPI00003949; -.
DR PaxDb; P61088; -.
DR PeptideAtlas; P61088; -.
DR PRIDE; P61088; -.
DR DNASU; 7334; -.
DR Ensembl; ENST00000318066; ENSP00000316176; ENSG00000177889.
DR GeneID; 7334; -.
DR KEGG; hsa:7334; -.
DR UCSC; uc001tcp.3; human.
DR CTD; 7334; -.
DR GeneCards; GC12M093735; -.
DR HGNC; HGNC:12492; UBE2N.
DR HPA; HPA003962; -.
DR MIM; 603679; gene.
DR neXtProt; NX_P61088; -.
DR PharmGKB; PA37141; -.
DR eggNOG; COG5078; -.
DR HOGENOM; HOG000233455; -.
DR HOVERGEN; HBG063308; -.
DR InParanoid; P61088; -.
DR KO; K10580; -.
DR OMA; DVAKHYK; -.
DR OrthoDB; EOG7XWPQB; -.
DR PhylomeDB; P61088; -.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P61088; -.
DR UniPathway; UPA00143; -.
DR ChiTaRS; UBE2N; human.
DR EvolutionaryTrace; P61088; -.
DR GeneWiki; UBE2N; -.
DR GenomeRNAi; 7334; -.
DR NextBio; 28704; -.
DR PRO; PR:P61088; -.
DR ArrayExpress; P61088; -.
DR Bgee; P61088; -.
DR CleanEx; HS_UBE2N; -.
DR Genevestigator; P61088; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0031372; C:UBC13-MMS2 complex; IDA:HGNC.
DR GO; GO:0035370; C:UBC13-UEV1A complex; IDA:UniProtKB.
DR GO; GO:0000151; C:ubiquitin ligase complex; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0043130; F:ubiquitin binding; IDA:HGNC.
DR GO; GO:0004842; F:ubiquitin-protein ligase activity; IDA:UniProtKB.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0000729; P:DNA double-strand break processing; IMP:HGNC.
DR GO; GO:0000724; P:double-strand break repair via homologous recombination; IMP:HGNC.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0016574; P:histone ubiquitination; IMP:HGNC.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0070423; P:nucleotide-binding oligomerization domain containing signaling pathway; TAS:Reactome.
DR GO; GO:0045739; P:positive regulation of DNA repair; IMP:HGNC.
DR GO; GO:0031058; P:positive regulation of histone modification; IMP:HGNC.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; IMP:HGNC.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IMP:UniProtKB.
DR GO; GO:0051443; P:positive regulation of ubiquitin-protein ligase activity; IMP:HGNC.
DR GO; GO:0006301; P:postreplication repair; IMP:HGNC.
DR GO; GO:0070534; P:protein K63-linked ubiquitination; IDA:UniProtKB.
DR GO; GO:0006508; P:proteolysis; TAS:ProtInc.
DR GO; GO:0033182; P:regulation of histone ubiquitination; IMP:HGNC.
DR GO; GO:0050852; P:T cell receptor signaling pathway; IMP:UniProtKB.
DR GO; GO:0034166; P:toll-like receptor 10 signaling pathway; TAS:Reactome.
DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; TAS:Reactome.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR GO; GO:0034146; P:toll-like receptor 5 signaling pathway; TAS:Reactome.
DR GO; GO:0034162; P:toll-like receptor 9 signaling pathway; TAS:Reactome.
DR GO; GO:0038123; P:toll-like receptor TLR1:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0038124; P:toll-like receptor TLR6:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IEA:Ensembl.
DR Gene3D; 3.10.110.10; -; 1.
DR InterPro; IPR000608; UBQ-conjugat_E2.
DR InterPro; IPR023313; UBQ-conjugating_AS.
DR InterPro; IPR016135; UBQ-conjugating_enzyme/RWD.
DR Pfam; PF00179; UQ_con; 1.
DR SUPFAM; SSF54495; SSF54495; 1.
DR PROSITE; PS00183; UBIQUITIN_CONJUGAT_1; 1.
DR PROSITE; PS50127; UBIQUITIN_CONJUGAT_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; ATP-binding; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Disulfide bond; DNA damage; DNA repair;
KW Isopeptide bond; Ligase; Nucleotide-binding; Nucleus;
KW Reference proteome; Ubl conjugation; Ubl conjugation pathway.
FT CHAIN 1 152 Ubiquitin-conjugating enzyme E2 N.
FT /FTId=PRO_0000082502.
FT ACT_SITE 87 87 Glycyl thioester intermediate.
FT MOD_RES 82 82 N6-acetyllysine.
FT DISULFID 87 87 Interchain (with C-78 in ISG15).
FT CROSSLNK 92 92 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ISG15).
FT MUTAGEN 87 87 C->A: Loss of polyubiquitination of PCNA.
FT Impairs interaction with SHPRH.
FT MUTAGEN 92 92 K->R: No ISGylation.
FT MUTAGEN 94 94 K->R: No effect on ISGylation.
FT HELIX 6 17
FT STRAND 23 27
FT STRAND 34 40
FT TURN 46 49
FT STRAND 51 57
FT TURN 60 63
FT STRAND 68 73
FT HELIX 89 91
FT TURN 92 94
FT HELIX 101 113
FT HELIX 124 131
FT HELIX 133 147
FT STRAND 148 150
SQ SEQUENCE 152 AA; 17138 MW; FACD84D883D77407 CRC64;
MAGLPRRIIK ETQRLLAEPV PGIKAEPDES NARYFHVVIA GPQDSPFEGG TFKLELFLPE
EYPMAAPKVR FMTKIYHPNV DKLGRICLDI LKDKWSPALQ IRTVLLSIQA LLSAPNPDDP
LANDVAEQWK TNEAQAIETA RAWTRLYAMN NI
//
MIM
603679
*RECORD*
*FIELD* NO
603679
*FIELD* TI
*603679 UBIQUITIN-CONJUGATING ENZYME E2N; UBE2N
;;UBIQUITIN-CONJUGATING ENZYME 13, S. CEREVISIAE, HOMOLOG OF; UBC13;;
read moreBENDLESS, DROSOPHILA, HOMOLOG OF; UBCHBEN
*FIELD* TX
CLONING
Yamaguchi et al. (1996) cloned the cDNA encoding UBE2N, a human
ubiquitin (191339)-conjugating enzyme, from an epidermoid carcinoma KB
cDNA library. The UBE2N gene, which the authors referred to as UBCHBEN,
encodes a protein of 152 amino acids with a calculated molecular mass of
17.1 kD. The amino acid sequence shows 80% identity with the Drosophila
'bendless' gene product (ubiquitin-conjugating enzyme E2). Northern blot
analysis detected a major 1.4- and a minor 2.4-kb transcript in all
tissues examined, with the highest expression in heart, skeletal muscle,
and testis.
GENE FUNCTION
Yamaguchi et al. (1996) found that, when expressed in Escherichia coli,
the UBE2N gene product exhibited the ability to form a thiol ester
linkage with ubiquitin in a ubiquitin-activating enzyme E1
(314370)-dependent manner. They concluded that the UBE2N gene encodes a
novel human E2 that may be involved in protein degradation in the
muscles and testis.
In yeast, Hofmann and Pickart (1999) showed that UBE2N, which they
referred to as UBC13, formed a specific heteromeric complex with MMS2, a
ubiquitin-conjugating enzyme variant (UBE2V2; 603001). A ubc13 yeast
strain was ultraviolet (UV) sensitive, and single, double, and triple
mutants of the UBC13, MMS2, and ubiquitin genes displayed a similar
phenotype. These findings supported a model in which an MMS2/UBC13
complex assembles novel polyubiquitin chains for signaling in DNA
repair, and suggested that UEV proteins may act to increase diversity
and selectivity in ubiquitin conjugation.
The RAD6 (179095) pathway is central to postreplicative DNA repair in
eukaryotic cells. Two principal elements of this pathway are the
ubiquitin-conjugating enzymes RAD6 and the MMS2-UBC13 heterodimer, which
are recruited to chromatin by the RING finger proteins RAD18 (605256)
and RAD5 (608048), respectively. Hoege et al. (2002) showed that UBC9
(601661), a small ubiquitin-related modifier (SUMO)-conjugating enzyme,
is also affiliated with this pathway and that proliferating cell nuclear
antigen (PCNA; 176740), a DNA polymerase sliding clamp involved in DNA
synthesis and repair, is a substrate. PCNA is monoubiquitinated through
RAD6 and RAD18, modified by lys63-linked multiubiquitination, which
additionally requires MMS2, UBC13, and RAD5, and is conjugated to SUMO
by UBC9. All 3 modifications affect the same lysine residue of PCNA,
K164, suggesting that they label PCNA for alternative functions. Hoege
et al. (2002) demonstrated that these modifications differentially
affect resistance to DNA damage, and that damage-induced PCNA
ubiquitination is elementary for DNA repair and occurs at the same
conserved residue in yeast and humans.
Zhao et al. (2007) found that depletion of UBC13 in chicken and human
cells resulted in severe growth defects due to chromosome instability,
as well as hypersensitivity to UV and ionizing radiation, consistent
with a conserved role for UBC13 in RAD6/RAD18-dependent postreplication
repair. UBC13-deficient cells were also compromised for DNA
double-strand break repair by homologous recombination. Recruitment and
activation of the E3 ubiquitin ligase function of BRCA1 (113705) and
subsequent formation of RAD51 (179617) nucleoprotein filaments at
double-strand breaks were abolished in UBC13-deficient cells.
Furthermore, in the absence of UBC13, generation of single-strand
DNA/RPA (see RPA1; 179835) complexes at double-strand breaks was
severely attenuated. Zhao et al. (2007) concluded that UBC13 has a role
in initiation of homologous recombination during double-strand break
repair.
Cytokine signaling is thought to require assembly of multicomponent
signaling complexes at cytoplasmic segments of membrane-embedded
receptors, in which receptor-proximal protein kinases are activated.
Matsuzawa et al. (2008) reported that, upon ligation, CD40 (109535)
formed a complex containing adaptor molecules TRAF2 (601895) and TRAF3
(601896), ubiquitin-conjugating enzyme UBC13, cellular inhibitor of
apoptosis protein-1 (CIAP1, or BIRC2; 601712) and -2 (CIAP2, or BIRC3;
601721), IKK-gamma (IKBKG; 300248), and MEKK1 (MAP3K1; 600982). TRAF2,
UBC13, and IKK-gamma were required for complex assembly and activation
of MEKK1 and MAP kinase cascades. However, the kinases were not
activated unless the complex was translocated from the membrane to the
cytosol upon CIAP1/CIAP2-induced degradation of TRAF3. Matsuzawa et al.
(2008) proposed that this 2-stage signaling mechanism may apply to other
innate immune receptors and may account for spatial and temporal
separation of MAPK and IKK signaling.
Shembade et al. (2010) showed that A20 (191163) inhibits the E3 ligase
activities of TRAF6 (602355), TRAF2, and cIAP1 by antagonizing
interactions with E2 ubiquitin-conjugating enzymes UBC13 and UBCH5C
(602963). A20, together with the regulatory molecule TAX1BP1 (605326),
interacted with UBC13 and UBCH5C and triggered their ubiquitination and
proteasome-dependent degradation. These findings suggested a mechanism
of A20 action in the inhibition of inflammatory signaling pathways.
Nakada et al. (2010) reported that OTUB1 (608337), a deubiquitinating
enzyme, is an inhibitor of double-stranded break-induced chromatin
ubiquitination. Surprisingly, they found that OTUB1 suppresses RNF168
(612688)-dependent polyubiquitination independently of its catalytic
activity. OTUB1 does so by binding to and inhibiting UBC13, the cognate
E2 enzyme for RNF168. Nakada et al. (2010) suggested that this unusual
mode of regulation is unlikely to be limited to UBC13 because analysis
of OTUB1-associated proteins revealed that OTUB1 binds to E2s of the
UBE2D and UBE2E subfamilies. Finally, OTUB1 depletion mitigates the
double-stranded break repair defect associated with defective ATM
(607585) signaling, indicating that pharmacologic targeting of the
OTUB1-UBC13 interaction might enhance the DNA damage response.
Pertel et al. (2011) demonstrated that TRIM5 (608487) promotes innate
immune signaling and that this activity is amplified by retroviral
infection and interaction with the capsid lattice. Acting with the
heterodimeric ubiquitin-conjugating enzyme UBC13-UEV1A (602995), TRIM5
catalyzes the synthesis of unattached K63-linked ubiquitin chains that
activate the TAK1 (602614) kinase complex and stimulate AP1 (see 165160)
and NF-kappa-B (see 164011) signaling. Interaction with the HIV-1 capsid
lattice greatly enhanced the UBC13-UEV1A-dependent E3 activity of TRIM5,
and challenge with retroviruses induced the transcription of AP1- and
NF-kappa-B-dependent factors with a magnitude that tracked with TRIM5
avidity for the invading capsid. Finally, TAK1 and UBC13-UEV1A
contribute to capsid-specific restriction by TRIM5. Pertel et al. (2011)
concluded that the retroviral restriction factor TRIM5 has 2 additional
activities that are linked to restriction: it constitutively promotes
innate immune signaling, and it acts as a pattern recognition receptor
specific for the retrovirus capsid lattice.
By infecting a human epithelial cell line with wildtype Shigella
flexneri or an S. flexneri mutant lacking the glutamine deamidase OspI,
Sanada et al. (2012) showed that OspI selectively deamidated gln100 of
UBC13 to glu. Consequently, the E2 ubiquitin-conjugating activity
required for TRAF6 activation was inhibited, allowing OspI to modulate
the diacylglycerol-NFKB signaling pathway, which is mediated through the
CARD11 (607210)-BCL10 (603517)-MALT1 (604860) (CBM) complex and TRAF6.
Sanada et al. (2012) proposed that S. flexneri inhibits acute
inflammatory responses by targeting the UBC13-TRAF6 complex.
BIOCHEMICAL FEATURES
- Crystal Structure
Wiener et al. (2012) described structural and biochemical studies
elucidating how OTUB1 inhibits UBC13 and other E2 enzymes. They
unexpectedly found that OTUB1 binding to UBC13-Ub (the ubiquitin
thiolester) is allosterically regulated by free ubiquitin, which binds
to a second site in OTUB1 and increases its affinity for UBC13-Ub, while
at the same time disrupting interactions with UEV1A in a manner that
depends on the OTUB1 N terminus. Crystal structures of an OTUB1-UBC13
complex and of OTUB1 bound to ubiquitin aldehyde and a chemical UBC13-Ub
conjugate showed that binding of free ubiquitin to OTUB1 triggers
conformational changes in the OTU domain and formation of a
ubiquitin-binding helix in the N terminus, thus promoting binding of the
conjugated donor ubiquitin in UBC13-Ub to OTUB1. The donor ubiquitin
thus cannot interact with the E2 enzyme, which has been shown to be
important for ubiquitin transfer. The N-terminal helix of OTUB1 is
positioned to interfere with UEV1A binding to UBC13, as well as with
attack on the thiolester by an acceptor ubiquitin, thereby inhibiting
K63Ub synthesis. OTUB1 binding also occludes the RING E3 binding site on
UBC13, thus providing a further component of inhibition. Wiener et al.
(2012) concluded that the general features of the inhibition mechanism
explained how OTUB1 inhibits other E2 enzymes in a noncatalytic manner.
ANIMAL MODEL
Yamamoto et al. (2006) generated mice with B cell-specific deletion of
Ubc13. These mice were viable and had no obvious abnormalities, whereas
Ubc13-deficient mice died early in utero. The absence of Ubc13 in B
cells resulted in defective development of marginal zone B cells and B1
cells, as well as impaired humoral immunity. Nfkb (see 164011)
activation and Tak1 (NR2C2; 601426) phosphorylation were essentially
normal in Ubc13-deficient cells, but MAP kinase activation was
substantially impaired in response to all stimuli tested except Tnf
(191160). Ubc13-induced MAP kinase activation was mediated partially
through ubiquitination of Ikkg, which was abolished in Ubc13-deficient
cells. Yamamoto et al. (2006) concluded that UBC13 is important in the
induction of immune responses.
Fukushima et al. (2007) found that homozygous Ubc13 deletion in mice
caused early embryonic lethality, whereas Ubc13 +/- heterozygotes
appeared normal with no alterations in immune cell populations. Ubc13
+/- mice resisted lipopolysaccharide-induced lethality, showed reduced
ubiquitination of Traf6 (602355), produced lower levels of Tnf, Il6
(147620), and Ifng (147570), and exhibited selectively impaired
activation of signal transduction pathways initiated by Tnfr and Tlr
family members. Fukushima et al. (2007) proposed that reducing UBC13
activity may have therapeutic uses in controlling inflammatory
responses.
*FIELD* RF
1. Fukushima, T.; Matsuzawa, S.; Kress, C. L.; Bruey, J. M.; Krajewska,
M.; Lefebvre, S.; Zapata, J. M.; Ronai, Z.; Reed, J. C.: Ubiquitin-conjugating
enzyme Ubc13 is a critical component of TNF receptor-associated factor
(TRAF)-mediated inflammatory responses. Proc. Nat. Acad. Sci. 104:
6371-6376, 2007.
2. Hoege, C.; Pfander, B.; Moldovan, G.-L.; Pyrowolakis, G.; Jentsch,
S.: RAD6-dependent DNA repair is linked to modification of PCNA by
ubiquitin and SUMO. Nature 419: 135-141, 2002.
3. Hofmann, R. M.; Pickart, C. M.: Noncanonical MMS2-encoded ubiquitin-conjugating
enzyme functions in assembly of novel polyubiquitin chains for DNA
repair. Cell 96: 645-653, 1999.
4. Matsuzawa, A.; Tseng, P.-H.; Vallabhapurapu, S.; Luo, J.-L.; Zhang,
W.; Wang, H.; Vignali, D. A. A.; Gallagher, E.; Karin, M.: Essential
cytoplasmic translocation of a cytokine receptor-assembled signaling
complex. Science 321: 663-668, 2008. Note: Erratum: Science 322:
375 only, 2008.
5. Nakada, S.; Tai, I.; Panier, S.; Al-Hakim, A.; Iemura, S.; Juang,
Y.-C.; O'Donnell, L.; Kumakubo, A.; Munro, M.; Sicheri, F.; Gingras,
A.-C.; Natsume, T.; Suda, T.; Durocher, D.: Non-canonical inhibition
of DNA damage-dependent ubiquitination by OTUB1. Nature 466: 941-946,
2010.
6. Pertel, T.; Hausmann, S.; Morger, D.; Zuger, S.; Guerra, J.; Lascano,
J.; Reinhard, C.; Santoni, F. A.; Uchil, P. D.; Chatel, L.; Bisiaux,
A.; Albert, M. L.; Strambio-De-Castillia, C.; Mothes, W.; Pizzato,
M.; Grutter, M. G.; Luban, J.: TRIM5 is an innate immune sensor for
the retrovirus capsid lattice. Nature 472: 361-365, 2011.
7. Sanada, T.; Kim, M.; Mimuro, H.; Suzuki, M.; Ogawa, M.; Oyama,
A.; Ashida, H.; Kobayashi, T.; Koyama, T.; Nagai, S.; Shibata, Y.;
Gohda, J.; Inoue, J.; Mizushima, T.; Sasakawa, C.: The Shigella flexneri
effector OspI deamidates UBC13 to dampen the inflammatory response. Nature 483:
623-626, 2012.
8. Shembade, N.; Ma, A.; Harhaj, E. W.: Inhibition of NF-kappa-B
signaling by A20 through disruption of ubiquitin enzyme complexes. Science 327:
1135-1139, 2010.
9. Wiener, R.; Zhang, X.; Wang, T.; Wolberger, C.: The mechanism
of OTUB1-mediated inhibition of ubiquitination. Nature 483: 618-622,
2012.
10. Yamaguchi, T.; Kim, N.-S.; Sekine, S.; Seino, H.; Osaka, F.; Yamao,
F.; Kato, S.: Cloning and expression of cDNA encoding a human ubiquitin-conjugating
enzyme similar to the Drosophila bendless gene product. J. Biochem. 120:
494-497, 1996.
11. Yamamoto, M.; Okamoto, T.; Takeda, K.; Sato, S.; Sanjo, H.; Uematsu,
S.; Saitoh, T.; Yamamoto, N.; Sakurai, H.; Ishii, K. J.; Yamaoka,
S.; Kawai, T.; Matsuura, Y.; Takeuchi, O.; Akira, S.: Key function
for the Ubc13 E2 ubiquitin-conjugating enzyme in immune receptor signaling. Nature
Immun. 7: 962-970, 2006.
12. Zhao, G. Y.; Sonoda, E.; Barber, L. J.; Oka, H.; Murakawa, Y.;
Yamada, K.; Ikura, T.; Wang, X.; Kobayashi, M.; Yamamoto, K.; Boulton,
S. J.; Takeda, S.: A critical role for the ubiquitin-conjugating
enzyme Ubc13 in initiating homologous recombination. Molec. Cell 25:
663-675, 2007.
*FIELD* CN
Ada Hamosh - updated: 5/15/2012
Paul J. Converse - updated: 4/12/2012
Ada Hamosh - updated: 7/8/2011
Ada Hamosh - updated: 9/21/2010
Ada Hamosh - updated: 3/9/2010
Paul J. Converse - updated: 8/28/2008
Paul J. Converse - updated: 7/2/2007
Patricia A. Hartz - updated: 4/16/2007
Paul J. Converse - updated: 1/5/2007
Ada Hamosh - updated: 9/30/2002
*FIELD* CD
Stylianos E. Antonarakis: 3/29/1999
*FIELD* ED
alopez: 05/16/2012
terry: 5/15/2012
mgross: 4/13/2012
terry: 4/12/2012
alopez: 7/12/2011
terry: 7/8/2011
alopez: 9/22/2010
terry: 9/21/2010
alopez: 3/11/2010
terry: 3/9/2010
alopez: 11/18/2008
mgross: 8/28/2008
mgross: 8/24/2007
mgross: 8/23/2007
terry: 7/2/2007
mgross: 4/19/2007
terry: 4/16/2007
alopez: 1/29/2007
mgross: 1/5/2007
carol: 5/12/2004
alopez: 10/1/2002
tkritzer: 9/30/2002
mgross: 3/31/1999
*RECORD*
*FIELD* NO
603679
*FIELD* TI
*603679 UBIQUITIN-CONJUGATING ENZYME E2N; UBE2N
;;UBIQUITIN-CONJUGATING ENZYME 13, S. CEREVISIAE, HOMOLOG OF; UBC13;;
read moreBENDLESS, DROSOPHILA, HOMOLOG OF; UBCHBEN
*FIELD* TX
CLONING
Yamaguchi et al. (1996) cloned the cDNA encoding UBE2N, a human
ubiquitin (191339)-conjugating enzyme, from an epidermoid carcinoma KB
cDNA library. The UBE2N gene, which the authors referred to as UBCHBEN,
encodes a protein of 152 amino acids with a calculated molecular mass of
17.1 kD. The amino acid sequence shows 80% identity with the Drosophila
'bendless' gene product (ubiquitin-conjugating enzyme E2). Northern blot
analysis detected a major 1.4- and a minor 2.4-kb transcript in all
tissues examined, with the highest expression in heart, skeletal muscle,
and testis.
GENE FUNCTION
Yamaguchi et al. (1996) found that, when expressed in Escherichia coli,
the UBE2N gene product exhibited the ability to form a thiol ester
linkage with ubiquitin in a ubiquitin-activating enzyme E1
(314370)-dependent manner. They concluded that the UBE2N gene encodes a
novel human E2 that may be involved in protein degradation in the
muscles and testis.
In yeast, Hofmann and Pickart (1999) showed that UBE2N, which they
referred to as UBC13, formed a specific heteromeric complex with MMS2, a
ubiquitin-conjugating enzyme variant (UBE2V2; 603001). A ubc13 yeast
strain was ultraviolet (UV) sensitive, and single, double, and triple
mutants of the UBC13, MMS2, and ubiquitin genes displayed a similar
phenotype. These findings supported a model in which an MMS2/UBC13
complex assembles novel polyubiquitin chains for signaling in DNA
repair, and suggested that UEV proteins may act to increase diversity
and selectivity in ubiquitin conjugation.
The RAD6 (179095) pathway is central to postreplicative DNA repair in
eukaryotic cells. Two principal elements of this pathway are the
ubiquitin-conjugating enzymes RAD6 and the MMS2-UBC13 heterodimer, which
are recruited to chromatin by the RING finger proteins RAD18 (605256)
and RAD5 (608048), respectively. Hoege et al. (2002) showed that UBC9
(601661), a small ubiquitin-related modifier (SUMO)-conjugating enzyme,
is also affiliated with this pathway and that proliferating cell nuclear
antigen (PCNA; 176740), a DNA polymerase sliding clamp involved in DNA
synthesis and repair, is a substrate. PCNA is monoubiquitinated through
RAD6 and RAD18, modified by lys63-linked multiubiquitination, which
additionally requires MMS2, UBC13, and RAD5, and is conjugated to SUMO
by UBC9. All 3 modifications affect the same lysine residue of PCNA,
K164, suggesting that they label PCNA for alternative functions. Hoege
et al. (2002) demonstrated that these modifications differentially
affect resistance to DNA damage, and that damage-induced PCNA
ubiquitination is elementary for DNA repair and occurs at the same
conserved residue in yeast and humans.
Zhao et al. (2007) found that depletion of UBC13 in chicken and human
cells resulted in severe growth defects due to chromosome instability,
as well as hypersensitivity to UV and ionizing radiation, consistent
with a conserved role for UBC13 in RAD6/RAD18-dependent postreplication
repair. UBC13-deficient cells were also compromised for DNA
double-strand break repair by homologous recombination. Recruitment and
activation of the E3 ubiquitin ligase function of BRCA1 (113705) and
subsequent formation of RAD51 (179617) nucleoprotein filaments at
double-strand breaks were abolished in UBC13-deficient cells.
Furthermore, in the absence of UBC13, generation of single-strand
DNA/RPA (see RPA1; 179835) complexes at double-strand breaks was
severely attenuated. Zhao et al. (2007) concluded that UBC13 has a role
in initiation of homologous recombination during double-strand break
repair.
Cytokine signaling is thought to require assembly of multicomponent
signaling complexes at cytoplasmic segments of membrane-embedded
receptors, in which receptor-proximal protein kinases are activated.
Matsuzawa et al. (2008) reported that, upon ligation, CD40 (109535)
formed a complex containing adaptor molecules TRAF2 (601895) and TRAF3
(601896), ubiquitin-conjugating enzyme UBC13, cellular inhibitor of
apoptosis protein-1 (CIAP1, or BIRC2; 601712) and -2 (CIAP2, or BIRC3;
601721), IKK-gamma (IKBKG; 300248), and MEKK1 (MAP3K1; 600982). TRAF2,
UBC13, and IKK-gamma were required for complex assembly and activation
of MEKK1 and MAP kinase cascades. However, the kinases were not
activated unless the complex was translocated from the membrane to the
cytosol upon CIAP1/CIAP2-induced degradation of TRAF3. Matsuzawa et al.
(2008) proposed that this 2-stage signaling mechanism may apply to other
innate immune receptors and may account for spatial and temporal
separation of MAPK and IKK signaling.
Shembade et al. (2010) showed that A20 (191163) inhibits the E3 ligase
activities of TRAF6 (602355), TRAF2, and cIAP1 by antagonizing
interactions with E2 ubiquitin-conjugating enzymes UBC13 and UBCH5C
(602963). A20, together with the regulatory molecule TAX1BP1 (605326),
interacted with UBC13 and UBCH5C and triggered their ubiquitination and
proteasome-dependent degradation. These findings suggested a mechanism
of A20 action in the inhibition of inflammatory signaling pathways.
Nakada et al. (2010) reported that OTUB1 (608337), a deubiquitinating
enzyme, is an inhibitor of double-stranded break-induced chromatin
ubiquitination. Surprisingly, they found that OTUB1 suppresses RNF168
(612688)-dependent polyubiquitination independently of its catalytic
activity. OTUB1 does so by binding to and inhibiting UBC13, the cognate
E2 enzyme for RNF168. Nakada et al. (2010) suggested that this unusual
mode of regulation is unlikely to be limited to UBC13 because analysis
of OTUB1-associated proteins revealed that OTUB1 binds to E2s of the
UBE2D and UBE2E subfamilies. Finally, OTUB1 depletion mitigates the
double-stranded break repair defect associated with defective ATM
(607585) signaling, indicating that pharmacologic targeting of the
OTUB1-UBC13 interaction might enhance the DNA damage response.
Pertel et al. (2011) demonstrated that TRIM5 (608487) promotes innate
immune signaling and that this activity is amplified by retroviral
infection and interaction with the capsid lattice. Acting with the
heterodimeric ubiquitin-conjugating enzyme UBC13-UEV1A (602995), TRIM5
catalyzes the synthesis of unattached K63-linked ubiquitin chains that
activate the TAK1 (602614) kinase complex and stimulate AP1 (see 165160)
and NF-kappa-B (see 164011) signaling. Interaction with the HIV-1 capsid
lattice greatly enhanced the UBC13-UEV1A-dependent E3 activity of TRIM5,
and challenge with retroviruses induced the transcription of AP1- and
NF-kappa-B-dependent factors with a magnitude that tracked with TRIM5
avidity for the invading capsid. Finally, TAK1 and UBC13-UEV1A
contribute to capsid-specific restriction by TRIM5. Pertel et al. (2011)
concluded that the retroviral restriction factor TRIM5 has 2 additional
activities that are linked to restriction: it constitutively promotes
innate immune signaling, and it acts as a pattern recognition receptor
specific for the retrovirus capsid lattice.
By infecting a human epithelial cell line with wildtype Shigella
flexneri or an S. flexneri mutant lacking the glutamine deamidase OspI,
Sanada et al. (2012) showed that OspI selectively deamidated gln100 of
UBC13 to glu. Consequently, the E2 ubiquitin-conjugating activity
required for TRAF6 activation was inhibited, allowing OspI to modulate
the diacylglycerol-NFKB signaling pathway, which is mediated through the
CARD11 (607210)-BCL10 (603517)-MALT1 (604860) (CBM) complex and TRAF6.
Sanada et al. (2012) proposed that S. flexneri inhibits acute
inflammatory responses by targeting the UBC13-TRAF6 complex.
BIOCHEMICAL FEATURES
- Crystal Structure
Wiener et al. (2012) described structural and biochemical studies
elucidating how OTUB1 inhibits UBC13 and other E2 enzymes. They
unexpectedly found that OTUB1 binding to UBC13-Ub (the ubiquitin
thiolester) is allosterically regulated by free ubiquitin, which binds
to a second site in OTUB1 and increases its affinity for UBC13-Ub, while
at the same time disrupting interactions with UEV1A in a manner that
depends on the OTUB1 N terminus. Crystal structures of an OTUB1-UBC13
complex and of OTUB1 bound to ubiquitin aldehyde and a chemical UBC13-Ub
conjugate showed that binding of free ubiquitin to OTUB1 triggers
conformational changes in the OTU domain and formation of a
ubiquitin-binding helix in the N terminus, thus promoting binding of the
conjugated donor ubiquitin in UBC13-Ub to OTUB1. The donor ubiquitin
thus cannot interact with the E2 enzyme, which has been shown to be
important for ubiquitin transfer. The N-terminal helix of OTUB1 is
positioned to interfere with UEV1A binding to UBC13, as well as with
attack on the thiolester by an acceptor ubiquitin, thereby inhibiting
K63Ub synthesis. OTUB1 binding also occludes the RING E3 binding site on
UBC13, thus providing a further component of inhibition. Wiener et al.
(2012) concluded that the general features of the inhibition mechanism
explained how OTUB1 inhibits other E2 enzymes in a noncatalytic manner.
ANIMAL MODEL
Yamamoto et al. (2006) generated mice with B cell-specific deletion of
Ubc13. These mice were viable and had no obvious abnormalities, whereas
Ubc13-deficient mice died early in utero. The absence of Ubc13 in B
cells resulted in defective development of marginal zone B cells and B1
cells, as well as impaired humoral immunity. Nfkb (see 164011)
activation and Tak1 (NR2C2; 601426) phosphorylation were essentially
normal in Ubc13-deficient cells, but MAP kinase activation was
substantially impaired in response to all stimuli tested except Tnf
(191160). Ubc13-induced MAP kinase activation was mediated partially
through ubiquitination of Ikkg, which was abolished in Ubc13-deficient
cells. Yamamoto et al. (2006) concluded that UBC13 is important in the
induction of immune responses.
Fukushima et al. (2007) found that homozygous Ubc13 deletion in mice
caused early embryonic lethality, whereas Ubc13 +/- heterozygotes
appeared normal with no alterations in immune cell populations. Ubc13
+/- mice resisted lipopolysaccharide-induced lethality, showed reduced
ubiquitination of Traf6 (602355), produced lower levels of Tnf, Il6
(147620), and Ifng (147570), and exhibited selectively impaired
activation of signal transduction pathways initiated by Tnfr and Tlr
family members. Fukushima et al. (2007) proposed that reducing UBC13
activity may have therapeutic uses in controlling inflammatory
responses.
*FIELD* RF
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M.; Lefebvre, S.; Zapata, J. M.; Ronai, Z.; Reed, J. C.: Ubiquitin-conjugating
enzyme Ubc13 is a critical component of TNF receptor-associated factor
(TRAF)-mediated inflammatory responses. Proc. Nat. Acad. Sci. 104:
6371-6376, 2007.
2. Hoege, C.; Pfander, B.; Moldovan, G.-L.; Pyrowolakis, G.; Jentsch,
S.: RAD6-dependent DNA repair is linked to modification of PCNA by
ubiquitin and SUMO. Nature 419: 135-141, 2002.
3. Hofmann, R. M.; Pickart, C. M.: Noncanonical MMS2-encoded ubiquitin-conjugating
enzyme functions in assembly of novel polyubiquitin chains for DNA
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4. Matsuzawa, A.; Tseng, P.-H.; Vallabhapurapu, S.; Luo, J.-L.; Zhang,
W.; Wang, H.; Vignali, D. A. A.; Gallagher, E.; Karin, M.: Essential
cytoplasmic translocation of a cytokine receptor-assembled signaling
complex. Science 321: 663-668, 2008. Note: Erratum: Science 322:
375 only, 2008.
5. Nakada, S.; Tai, I.; Panier, S.; Al-Hakim, A.; Iemura, S.; Juang,
Y.-C.; O'Donnell, L.; Kumakubo, A.; Munro, M.; Sicheri, F.; Gingras,
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J.; Reinhard, C.; Santoni, F. A.; Uchil, P. D.; Chatel, L.; Bisiaux,
A.; Albert, M. L.; Strambio-De-Castillia, C.; Mothes, W.; Pizzato,
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the retrovirus capsid lattice. Nature 472: 361-365, 2011.
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A.; Ashida, H.; Kobayashi, T.; Koyama, T.; Nagai, S.; Shibata, Y.;
Gohda, J.; Inoue, J.; Mizushima, T.; Sasakawa, C.: The Shigella flexneri
effector OspI deamidates UBC13 to dampen the inflammatory response. Nature 483:
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8. Shembade, N.; Ma, A.; Harhaj, E. W.: Inhibition of NF-kappa-B
signaling by A20 through disruption of ubiquitin enzyme complexes. Science 327:
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9. Wiener, R.; Zhang, X.; Wang, T.; Wolberger, C.: The mechanism
of OTUB1-mediated inhibition of ubiquitination. Nature 483: 618-622,
2012.
10. Yamaguchi, T.; Kim, N.-S.; Sekine, S.; Seino, H.; Osaka, F.; Yamao,
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enzyme similar to the Drosophila bendless gene product. J. Biochem. 120:
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11. Yamamoto, M.; Okamoto, T.; Takeda, K.; Sato, S.; Sanjo, H.; Uematsu,
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*FIELD* CN
Ada Hamosh - updated: 5/15/2012
Paul J. Converse - updated: 4/12/2012
Ada Hamosh - updated: 7/8/2011
Ada Hamosh - updated: 9/21/2010
Ada Hamosh - updated: 3/9/2010
Paul J. Converse - updated: 8/28/2008
Paul J. Converse - updated: 7/2/2007
Patricia A. Hartz - updated: 4/16/2007
Paul J. Converse - updated: 1/5/2007
Ada Hamosh - updated: 9/30/2002
*FIELD* CD
Stylianos E. Antonarakis: 3/29/1999
*FIELD* ED
alopez: 05/16/2012
terry: 5/15/2012
mgross: 4/13/2012
terry: 4/12/2012
alopez: 7/12/2011
terry: 7/8/2011
alopez: 9/22/2010
terry: 9/21/2010
alopez: 3/11/2010
terry: 3/9/2010
alopez: 11/18/2008
mgross: 8/28/2008
mgross: 8/24/2007
mgross: 8/23/2007
terry: 7/2/2007
mgross: 4/19/2007
terry: 4/16/2007
alopez: 1/29/2007
mgross: 1/5/2007
carol: 5/12/2004
alopez: 10/1/2002
tkritzer: 9/30/2002
mgross: 3/31/1999