UBE4_CAEEL
ID UBE4_CAEEL Reviewed; 984 AA.
AC Q09349; Q6BEV4; Q95QB5;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 12-SEP-2018, sequence version 2.
DT 03-AUG-2022, entry version 124.
DE RecName: Full=Ubiquitin conjugation factor E4 ufd-2 {ECO:0000305};
DE EC=2.3.2.27 {ECO:0000269|PubMed:15294159, ECO:0000269|PubMed:27669035, ECO:0000269|PubMed:29396393};
DE AltName: Full=E4 ubiquitin-protein ligase ufd-2 {ECO:0000305};
DE AltName: Full=RING-type E3 ubiquitin transferase E4;
DE AltName: Full=Ubiquitin fusion degradation protein 2 {ECO:0000312|WormBase:T05H10.5b};
GN Name=ufd-2 {ECO:0000303|PubMed:15294159, ECO:0000312|WormBase:T05H10.5b};
GN ORFNames=T05H10.5 {ECO:0000312|WormBase:T05H10.5b};
OS Caenorhabditis elegans.
OC Eukaryota; Metazoa; Ecdysozoa; Nematoda; Chromadorea; Rhabditida;
OC Rhabditina; Rhabditomorpha; Rhabditoidea; Rhabditidae; Peloderinae;
OC Caenorhabditis.
OX NCBI_TaxID=6239;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Bristol N2;
RX PubMed=9851916; DOI=10.1126/science.282.5396.2012;
RG The C. elegans sequencing consortium;
RT "Genome sequence of the nematode C. elegans: a platform for investigating
RT biology.";
RL Science 282:2012-2018(1998).
RN [2]
RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, IDENTIFICATION IN A COMPLEX WITH
RP CHN-1 AND UNC-45, INTERACTION WITH CHN-1 AND UNC-45, DEVELOPMENTAL STAGE,
RP AND DOMAIN.
RX PubMed=15294159; DOI=10.1016/j.cell.2004.07.014;
RA Hoppe T., Cassata G., Barral J.M., Springer W., Hutagalung A.H.,
RA Epstein H.F., Baumeister R.;
RT "Regulation of the myosin-directed chaperone UNC-45 by a novel E3/E4-
RT multiubiquitylation complex in C. elegans.";
RL Cell 118:337-349(2004).
RN [3]
RP FUNCTION, IDENTIFICATION IN A COMPLEX WITH CDC-48.1; CHN-1 AND UNC-45,
RP INTERACTION WITH CDC-48.1; CDC-48.2; CHN-1 AND UNC-45, DEVELOPMENTAL STAGE,
RP AND DISRUPTION PHENOTYPE.
RX PubMed=17369820; DOI=10.1038/ncb1554;
RA Janiesch P.C., Kim J., Mouysset J., Barikbin R., Lochmueller H.,
RA Cassata G., Krause S., Hoppe T.;
RT "The ubiquitin-selective chaperone CDC-48/p97 links myosin assembly to
RT human myopathy.";
RL Nat. Cell Biol. 9:379-390(2007).
RN [4]
RP IDENTIFICATION IN A COMPLEX WITH ATX-3 AND CDC-48.1, AND INTERACTION WITH
RP ATX-3; CDC-48.1 AND CDC-48.2.
RX PubMed=21317884; DOI=10.1038/ncb2200;
RA Kuhlbrodt K., Janiesch P.C., Kevei E., Segref A., Barikbin R., Hoppe T.;
RT "The Machado-Joseph disease deubiquitylase ATX-3 couples longevity and
RT proteostasis.";
RL Nat. Cell Biol. 13:273-281(2011).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, INTERACTION WITH CDC-48.1,
RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, DISRUPTION PHENOTYPE, AND
RP MUTAGENESIS OF CYS-448 AND PRO-951.
RX PubMed=27669035; DOI=10.1038/nsmb.3296;
RA Ackermann L., Schell M., Pokrzywa W., Kevei E., Gartner A., Schumacher B.,
RA Hoppe T.;
RT "E4 ligase-specific ubiquitination hubs coordinate DNA double-strand-break
RT repair and apoptosis.";
RL Nat. Struct. Mol. Biol. 23:995-1002(2016).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, IDENTIFICATION IN A COMPLEX WITH
RP UNC-45 AND UNC-54, AND INTERACTION WITH UNC-45 AND UNC-54.
RX PubMed=29396393; DOI=10.1038/s41467-018-02924-7;
RA Hellerschmied D., Roessler M., Lehner A., Gazda L., Stejskal K., Imre R.,
RA Mechtler K., Dammermann A., Clausen T.;
RT "UFD-2 is an adaptor-assisted E3 ligase targeting unfolded proteins.";
RL Nat. Commun. 9:484-484(2018).
CC -!- FUNCTION: Acts as an E4 ubiquitin ligase mediating the assembly of
CC polyubiquitin chains on substrates ubiquitinated by another E3
CC ubiquitin ligase (PubMed:27669035). The elongation of preexisting
CC ubiquitin chains preferentially targets ubiquitin 'Lys-29' and 'Lys-48'
CC residues (PubMed:27669035). Also functions as an E3 ligase in
CC conjunction with specific E1 and E2 ligases (PubMed:15294159,
CC PubMed:27669035, PubMed:29396393). Probably by regulating protein
CC ubiquitination at DNA damage repair sites, coordinates DNA double-
CC strand-break repair and apoptosis in the germline (PubMed:27669035).
CC Required for germline apoptosis in response to DNA damage downstream of
CC cep-1 (PubMed:27669035). Involved in the resolution of DNA-repair sites
CC by promoting the release of rad-51 from DNA damage foci
CC (PubMed:27669035). In association with protein-ligase chn-1, acts as an
CC E3/E4 ligase to poly-ubiquitinate lysine residues in the UCS domain of
CC myosin chaperone unc-45 (PubMed:15294159, PubMed:29396393). By
CC targeting myosin chaperone unc-45 for proteasomal degradation,
CC regulates myosin assembly in body wall muscles in association with cdc-
CC 48.1 and chn-1 (PubMed:15294159, PubMed:17369820). However, in a
CC contrasting study, acts as an E3 ligase, independently of chn-1, to
CC poly-ubiquitinate unc-45 without promoting unc-45 proteasomal
CC degradation (PubMed:29396393). Instead, uses unc-45 as an adapter
CC protein to recruit and poly-ubiquitinate unfolded myosin heavy chain B
CC unc-54 (PubMed:29396393). {ECO:0000269|PubMed:15294159,
CC ECO:0000269|PubMed:17369820, ECO:0000269|PubMed:27669035,
CC ECO:0000269|PubMed:29396393}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine +
CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-
CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.;
CC EC=2.3.2.27; Evidence={ECO:0000269|PubMed:15294159,
CC ECO:0000269|PubMed:27669035, ECO:0000269|PubMed:29396393};
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000269|PubMed:15294159, ECO:0000269|PubMed:27669035,
CC ECO:0000269|PubMed:29396393}.
CC -!- SUBUNIT: Forms a complex composed of deubiquitinating enzyme atx-3, E4
CC ubiquitin-protein ligase ufd-2 and cdc-48.1; within the complex
CC interacts with atx-3 and cdc-48.1 (via DDDLYN motif) (PubMed:21317884,
CC PubMed:27669035). Forms a complex composed of cdc-48.1, myosin
CC chaperone unc-45, ubiquitin-protein ligases ufd-2 and chn-1; the
CC complex targets myosin chaperone unc-45 for proteasomal degradation;
CC within the complex interacts with cdc-48.1 (via DDDLYN motif), chn-1
CC and unc-45 (PubMed:17369820, PubMed:15294159, PubMed:27669035). Forms a
CC complex composed of unc-45 and myosin heavy chain B unc-54; the complex
CC targets unfolded unc-54 for proteasomal degradation; within the complex
CC interacts with unc-45 (via TPR domain) and unc-54 (PubMed:29396393).
CC Interacts with cdc-48.2 (via DDDLYN motif) (PubMed:21317884,
CC PubMed:17369820). {ECO:0000269|PubMed:15294159,
CC ECO:0000269|PubMed:17369820, ECO:0000269|PubMed:21317884,
CC ECO:0000269|PubMed:27669035, ECO:0000269|PubMed:29396393}.
CC -!- INTERACTION:
CC Q09349; P90879: CELE_F49C12.9; NbExp=4; IntAct=EBI-317233, EBI-2417964;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:27669035}. Nucleus
CC membrane {ECO:0000269|PubMed:27669035}; Peripheral membrane protein
CC {ECO:0000269|PubMed:27669035}; Cytoplasmic side
CC {ECO:0000269|PubMed:27669035}. Nucleus, nucleolus
CC {ECO:0000269|PubMed:27669035}. Note=Localizes to germline syncytium. In
CC the late pachytene, accumulates at the nuclear periphery forming a
CC ring. Following ionizing radiation-mediated DNA damage, localizes to
CC foci within nucleoli where it colocalizes with cdc-48.1 and/or cdc-
CC 48.2, atx-3, proteasome alpha subunit and ubiquitinated proteins.
CC Localization to foci is ubiquitin-dependent and regulated by E3 ligase
CC hecd-1 and deubiquitinating enzyme atx-3. ufd-2 foci are formed
CC following the initiation of homologous recombination (HR) and persist
CC until HR is completed. ufd-2 foci are also formed upon cep-1
CC activation. {ECO:0000269|PubMed:27669035}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=b {ECO:0000312|WormBase:T05H10.5b};
CC IsoId=Q09349-1; Sequence=Displayed;
CC Name=a {ECO:0000312|WormBase:T05H10.5a};
CC IsoId=Q09349-3; Sequence=VSP_059812;
CC Name=c {ECO:0000312|WormBase:T05H10.5c};
CC IsoId=Q09349-4; Sequence=VSP_059812, VSP_059813;
CC -!- TISSUE SPECIFICITY: Expressed in the germline (at protein level).
CC {ECO:0000269|PubMed:27669035}.
CC -!- DEVELOPMENTAL STAGE: Expressed in young adults but not in larvae
CC (PubMed:17369820). Expressed in pharyngeal muscles and in body wall
CC muscles in L2 and L4 larvae, respectively (PubMed:15294159).
CC {ECO:0000269|PubMed:15294159, ECO:0000269|PubMed:17369820}.
CC -!- DOMAIN: The U-box domain is required for the ubiquitin protein ligase
CC activity. {ECO:0000269|PubMed:15294159}.
CC -!- DISRUPTION PHENOTYPE: Number of germline apoptotic corpses is decreased
CC in response to ionizing radiation-mediated DNA damage but not following
CC UV-induced DNA damage (PubMed:27669035). Delay in the dissociation of
CC rad-51 from DNA damage foci (PubMed:27669035). In a hecd-1 (tm2371)
CC mutant background, the decrease in the number of germline apoptotic
CC corpses is more severe (PubMed:27669035). In an atx-3 (gk193) mutant
CC background, prevents the increase in the number of germline apoptotic
CC corpses (PubMed:27669035). RNAi-mediated knockdown in an unc-45 (m94)
CC mutant background restores motility (PubMed:17369820).
CC {ECO:0000269|PubMed:17369820, ECO:0000269|PubMed:27669035}.
CC -!- SIMILARITY: Belongs to the ubiquitin conjugation factor E4 family.
CC {ECO:0000305}.
CC -!- CAUTION: The role of chn-1 in ufd-2-mediated unc-45 ubiquitination is
CC controversial. While two studies showed that unc-45 ubiquitination by
CC ufd-2 requires ubiquitin-protein ligase chn-1, one study showed that
CC ufd-2 ubiquitinates unc-45 independently of chn-1.
CC {ECO:0000269|PubMed:15294159, ECO:0000269|PubMed:17369820,
CC ECO:0000269|PubMed:29396393}.
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DR EMBL; Z47812; CAA87792.1; -; Genomic_DNA.
DR EMBL; BX284602; CAC70105.1; -; Genomic_DNA.
DR EMBL; BX284602; CAH04720.1; -; Genomic_DNA.
DR PIR; T24556; T24556.
DR RefSeq; NP_001022320.1; NM_001027149.3. [Q09349-4]
DR RefSeq; NP_495691.1; NM_063290.1. [Q09349-1]
DR RefSeq; NP_495692.1; NM_063291.3.
DR AlphaFoldDB; Q09349; -.
DR SMR; Q09349; -.
DR BioGRID; 39626; 10.
DR DIP; DIP-25769N; -.
DR IntAct; Q09349; 1.
DR STRING; 6239.T05H10.5b; -.
DR EPD; Q09349; -.
DR PaxDb; Q09349; -.
DR PeptideAtlas; Q09349; -.
DR PRIDE; Q09349; -.
DR EnsemblMetazoa; T05H10.5a.1; T05H10.5a.1; WBGene00006734. [Q09349-3]
DR EnsemblMetazoa; T05H10.5b.1; T05H10.5b.1; WBGene00006734. [Q09349-1]
DR EnsemblMetazoa; T05H10.5c.1; T05H10.5c.1; WBGene00006734. [Q09349-4]
DR GeneID; 174295; -.
DR KEGG; cel:CELE_T05H10.5; -.
DR UCSC; T05H10.5a; c. elegans. [Q09349-1]
DR CTD; 174295; -.
DR WormBase; T05H10.5a; CE01642; WBGene00006734; ufd-2. [Q09349-3]
DR WormBase; T05H10.5b; CE28868; WBGene00006734; ufd-2. [Q09349-1]
DR WormBase; T05H10.5c; CE36948; WBGene00006734; ufd-2. [Q09349-4]
DR eggNOG; KOG2042; Eukaryota.
DR GeneTree; ENSGT00390000009300; -.
DR HOGENOM; CLU_003224_2_1_1; -.
DR InParanoid; Q09349; -.
DR OMA; LRWELHS; -.
DR OrthoDB; 194967at2759; -.
DR BRENDA; 2.3.2.27; 1045.
DR BRENDA; 2.3.2.B12; 1045.
DR SignaLink; Q09349; -.
DR UniPathway; UPA00143; -.
DR PRO; PR:Q09349; -.
DR Proteomes; UP000001940; Chromosome II.
DR Bgee; WBGene00006734; Expressed in adult organism and 3 other tissues.
DR GO; GO:0005737; C:cytoplasm; IDA:WormBase.
DR GO; GO:0031965; C:nuclear membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005730; C:nucleolus; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IDA:WormBase.
DR GO; GO:0000151; C:ubiquitin ligase complex; IEA:InterPro.
DR GO; GO:0051087; F:chaperone binding; IPI:WormBase.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:WormBase.
DR GO; GO:0034450; F:ubiquitin-ubiquitin ligase activity; IDA:WormBase.
DR GO; GO:0008340; P:determination of adult lifespan; IMP:UniProtKB.
DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IMP:UniProtKB.
DR GO; GO:0051865; P:protein autoubiquitination; IDA:WormBase.
DR GO; GO:0035519; P:protein K29-linked ubiquitination; IDA:WormBase.
DR GO; GO:0070936; P:protein K48-linked ubiquitination; IDA:WormBase.
DR GO; GO:0000209; P:protein polyubiquitination; IDA:WormBase.
DR GO; GO:0016567; P:protein ubiquitination; IDA:WormBase.
DR GO; GO:0030433; P:ubiquitin-dependent ERAD pathway; IBA:GO_Central.
DR Gene3D; 3.30.40.10; -; 1.
DR InterPro; IPR019474; Ub_conjug_fac_E4_core.
DR InterPro; IPR045132; UBE4.
DR InterPro; IPR003613; Ubox_domain.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR PANTHER; PTHR13931; PTHR13931; 1.
DR Pfam; PF04564; U-box; 1.
DR Pfam; PF10408; Ufd2P_core; 1.
DR SMART; SM00504; Ubox; 1.
DR PROSITE; PS51698; U_BOX; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cytoplasm; Membrane; Nucleus; Reference proteome;
KW Transferase; Ubl conjugation pathway.
FT CHAIN 1..984
FT /note="Ubiquitin conjugation factor E4 ufd-2"
FT /id="PRO_0000194995"
FT DOMAIN 909..982
FT /note="U-box"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01034"
FT VAR_SEQ 20..23
FT /note="Missing (in isoform a and isoform c)"
FT /evidence="ECO:0000305"
FT /id="VSP_059812"
FT VAR_SEQ 436
FT /note="Missing (in isoform c)"
FT /id="VSP_059813"
FT MUTAGEN 448
FT /note="C->Y: Loss of interaction with cdc-48.1.
FT Constitutive localization to foci. Decrease in the number
FT of apoptotic corpses in the germline in response to
FT ionizing radiation-mediated DNA damage. No defect in
FT catalytic activity."
FT /evidence="ECO:0000269|PubMed:27669035"
FT MUTAGEN 951
FT /note="P->A: Loss of E3 ubiquitin protein ligase activity.
FT Decrease in the number of apoptotic corpses in the germline
FT in response to ionizing radiation-mediated DNA damage. Does
FT not affect foci localization in response to ionizing
FT radiation-mediated DNA damage. Does not affect recruitment
FT of cdc-48, atx-3 or proteasome to foci. Does not affect
FT interaction with cdc-48.1."
FT /evidence="ECO:0000269|PubMed:27669035"
SQ SEQUENCE 984 AA; 113801 MW; 798FF0EF3A9BDA5B CRC64;
MIEDEKAGLQ PMDISDASVF FFQADVESKD FLTSLFDCEG KSDDRMLRYA DAIIDVQNLN
FDVSPQCLQS NIAEIITKFV LLSQDGSRRG LSRSFNFIDP DIIAGCREED AIEFLLINFV
RCHHELGKSG TSNCYKKTLE STRKAVFSVF VMIQRGYLES QLRSQHASLV FTKRLLEDTV
SNVFLRTLVE YLASTDECDE DAITETFNPI FGILRSGIIC QRFEDNKDEI VRQILRVMNL
LLSIRLPSNG PRPLSNLLVN REDFLPTPSE KIQGREFGLM SFLGPFFSYG LESSARRPNH
RVFVDCEEDA RKYDGSVNTE QKLYFQRMDP IRTMLHQLML PLASDQGSRN KTLRWIATII
STNDIRTRSH YDPSDVLCDH YMTNFLSVMY MFSEKIDLSK IIVDYPFLPS SLINISKETR
LKMDESGAVA FASQFADRPD EYHFSTVCFF LTIAAQRLVI PPLMNQISEY SRHLKELKHK
INALKEKLNT VSGFERAEVE KKLNYETEHW KLMSRHLLCV KTQAQDPALM ASSMDFVDKQ
MKFILNLLCD NLDLLGDDSQ LPTEVSQMFC ALPEYFLEDA LDFYIFAISN GMKLLMERNA
DWISRLTVLF TQYHYIKSPF LVSKLVRVLS SIQPPLWFNV VRLRMAQENL LMCMIKFYSD
FEDNGDFYEK FNVRGNIQYM LEKMEEDMFY KGKFMDMARE CGAEFIRFVN MVINDATWCI
DESLSGLKSI HDVEKKMANK VEWDNTDQEI RNQDLGVYEE AKRKVKGWLG TAKSNLKLLL
SITVNSPEPF RTPVLGERLA AMLNHNLSQL IGSKASELKV KDPRSYGWEP REFVSLLISI
YLKLNMPAFV KYIAYDERTY SPEFFHNAIE CMRKNSIVGF SQLESFEHLA EDVKKEYEAK
AELEEEYDDV PEEFKDPIMD AIMVDPVKLP SGHVMDRAVI ERHLLSTPNN PFNRAPLSHN
ELSPDSELKA KIQEWICQKR NSKK
