HUWE1_RAT
ID HUWE1_RAT Reviewed; 322 AA.
AC P51593;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 19-JUL-2004, sequence version 2.
DT 03-AUG-2022, entry version 134.
DE RecName: Full=E3 ubiquitin-protein ligase HUWE1;
DE EC=2.3.2.26;
DE AltName: Full=HECT, UBA and WWE domain-containing protein 1;
DE AltName: Full=HECT-type E3 ubiquitin transferase HUWE1;
DE AltName: Full=Upstream regulatory element-binding protein 1;
DE Short=URE-B1;
DE Short=URE-binding protein 1;
DE Flags: Fragment;
GN Name=Huwe1; Synonyms=Ureb1;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND SUBCELLULAR LOCATION.
RC TISSUE=Brain;
RX PubMed=7968380; DOI=10.1016/0169-328x(94)90120-1;
RA Gu J., Ren K., Dubner R., Iadarola M.J.;
RT "Cloning of a DNA binding protein that is a tyrosine kinase substrate and
RT recognizes an upstream initiator-like sequence in the promoter of the
RT preprodynorphin gene.";
RL Brain Res. Mol. Brain Res. 24:77-88(1994).
RN [2]
RP FUNCTION, PHOSPHORYLATION AT TYR-219, AND MUTAGENESIS OF TYR-219.
RX PubMed=7478539;
RA Gu J., Dubner R., Fornace A.J. Jr., Iadarola M.J.;
RT "UREB1, a tyrosine phosphorylated nuclear protein, inhibits p53
RT transactivation.";
RL Oncogene 11:2175-2178(1995).
RN [3]
RP TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RX PubMed=17823942; DOI=10.1002/dvdy.21302;
RA Liu Z., Miao D., Xia Q., Hermo L., Wing S.S.;
RT "Regulated expression of the ubiquitin protein ligase,
RT E3(Histone)/LASU1/Mule/ARF-BP1/HUWE1, during spermatogenesis.";
RL Dev. Dyn. 236:2889-2898(2007).
CC -!- FUNCTION: E3 ubiquitin-protein ligase which mediates ubiquitination and
CC subsequent proteasomal degradation of target proteins (By similarity).
CC Regulates apoptosis by catalyzing the polyubiquitination and
CC degradation of MCL1 (By similarity). Mediates monoubiquitination of DNA
CC polymerase beta (POLB) at 'Lys-41', 'Lys-61' and 'Lys-81', thereby
CC playing a role in base-excision repair (By similarity). Also
CC ubiquitinates the p53/TP53 tumor suppressor and core histones including
CC H1, H2A, H2B, H3 and H4 (PubMed:7478539). Ubiquitinates MFN2 to
CC negatively regulate mitochondrial fusion in response to decreased
CC stearoylation of TFRC (By similarity). Ubiquitination of MFN2 also
CC takes place following induction of mitophagy; AMBRA1 acts as a cofactor
CC for HUWE1-mediated ubiquitination (By similarity). Regulates neural
CC differentiation and proliferation by catalyzing the polyubiquitination
CC and degradation of MYCN (By similarity). May regulate abundance of CDC6
CC after DNA damage by polyubiquitinating and targeting CDC6 to
CC degradation (By similarity). Mediates polyubiquitination of PA2G4 (By
CC similarity). Acts in concert with MYCBP2 to regulate the circadian
CC clock gene expression by promoting the lithium-induced ubiquination and
CC degradation of NR1D1 (By similarity). Binds to an upstream initiator-
CC like sequence in the preprodynorphin gene (PubMed:7968380).
CC {ECO:0000250|UniProtKB:Q7Z6Z7, ECO:0000269|PubMed:7478539,
CC ECO:0000269|PubMed:7968380}.
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=2.3.2.26; Evidence={ECO:0000250|UniProtKB:Q7Z6Z7};
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000250|UniProtKB:Q7Z6Z7}.
CC -!- SUBUNIT: Interacts with isoform p14ARF of CDKN2A which strongly
CC inhibits HUWE1 ubiquitin ligase activity. Interacts with MYCN, POLB and
CC CDC6. Interacts with isoform 2 of PA2G4. Interacts with NR1D1.
CC Interacts with AMBRA1 (By similarity). {ECO:0000250|UniProtKB:Q7Z6Z7}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q7Z6Z7}. Nucleus
CC {ECO:0000269|PubMed:7968380}. Mitochondrion
CC {ECO:0000250|UniProtKB:Q7Z6Z7}. Note=Mainly expressed in the cytoplasm
CC of most tissues, except in the nucleus of spermatogonia, primary
CC spermatocytes and neuronal cells (By similarity). Recruited to
CC mitochondria following interaction with AMBRA1 (By similarity).
CC {ECO:0000250|UniProtKB:Q7TMY8, ECO:0000250|UniProtKB:Q7Z6Z7}.
CC -!- TISSUE SPECIFICITY: Widely expressed. {ECO:0000269|PubMed:17823942}.
CC -!- DEVELOPMENTAL STAGE: During spermatogenesis highest expression at
CC postnatal day 10 and then gradually decreases to day 40, after which it
CC remains constant at low levels. Protein peaks at postnatal day 20, and
CC then gradually decreases by day 45. {ECO:0000269|PubMed:17823942}.
CC -!- DOMAIN: The HECT domain mediates inhibition of the transcriptional
CC activity of p53. {ECO:0000250|UniProtKB:Q7Z6Z7}.
CC -!- PTM: Phosphorylated on tyrosine, phosphorylation is probably required
CC for its ability to inhibit TP53 transactivation.
CC {ECO:0000250|UniProtKB:Q7Z6Z7}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA81950.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; U08214; AAA81950.1; ALT_FRAME; mRNA.
DR AlphaFoldDB; P51593; -.
DR SMR; P51593; -.
DR STRING; 10116.ENSRNOP00000003882; -.
DR iPTMnet; P51593; -.
DR jPOST; P51593; -.
DR PaxDb; P51593; -.
DR PRIDE; P51593; -.
DR RGD; 1561763; Huwe1.
DR eggNOG; KOG0939; Eukaryota.
DR InParanoid; P51593; -.
DR PhylomeDB; P51593; -.
DR UniPathway; UPA00143; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0000139; C:Golgi membrane; IBA:GO_Central.
DR GO; GO:0005739; C:mitochondrion; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0003677; F:DNA binding; IDA:UniProtKB.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; ISS:UniProtKB.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; ISS:UniProtKB.
DR GO; GO:0006284; P:base-excision repair; ISS:UniProtKB.
DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR GO; GO:0032922; P:circadian regulation of gene expression; ISS:UniProtKB.
DR GO; GO:0007030; P:Golgi organization; IBA:GO_Central.
DR GO; GO:0016574; P:histone ubiquitination; ISS:UniProtKB.
DR GO; GO:0061025; P:membrane fusion; IBA:GO_Central.
DR GO; GO:0010637; P:negative regulation of mitochondrial fusion; ISO:RGD.
DR GO; GO:0098779; P:positive regulation of mitophagy in response to mitochondrial depolarization; ISO:RGD.
DR GO; GO:0031398; P:positive regulation of protein ubiquitination; ISS:UniProtKB.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IBA:GO_Central.
DR GO; GO:0006513; P:protein monoubiquitination; ISS:UniProtKB.
DR GO; GO:0000209; P:protein polyubiquitination; ISS:UniProtKB.
DR GO; GO:0016567; P:protein ubiquitination; IBA:GO_Central.
DR CDD; cd00078; HECTc; 1.
DR InterPro; IPR000569; HECT_dom.
DR InterPro; IPR035983; Hect_E3_ubiquitin_ligase.
DR Pfam; PF00632; HECT; 1.
DR SMART; SM00119; HECTc; 1.
DR SUPFAM; SSF56204; SSF56204; 1.
DR PROSITE; PS50237; HECT; 1.
PE 1: Evidence at protein level;
KW Biological rhythms; Cytoplasm; Differentiation; DNA damage; DNA repair;
KW DNA-binding; Mitochondrion; Nucleus; Phosphoprotein; Reference proteome;
KW Transferase; Ubl conjugation pathway.
FT CHAIN <1..322
FT /note="E3 ubiquitin-protein ligase HUWE1"
FT /id="PRO_0000120342"
FT DOMAIN <1..322
FT /note="HECT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00104"
FT ACT_SITE 289
FT /note="Glycyl thioester intermediate"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00104"
FT MOD_RES 219
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000305|PubMed:7478539"
FT MUTAGEN 219
FT /note="Y->D: Abolishes its ability to inhibit
FT transactivation of TP53."
FT /evidence="ECO:0000269|PubMed:7478539"
FT NON_TER 1
SQ SEQUENCE 322 AA; 37361 MW; E7794791E7AB3AF3 CRC64;
EEGQDAGGLL REWYMIISRE MFNPMYALFR TSPGDRVTYT INPSSHCNPN HLSYFKFVGR
IVAKAVYDNR LLECYFTRSF YKHILGKSVR YTDMESEDYH FYQGLVYLLE NDVSTLGYDL
TFSTEVQEFG VCEVRDLKPN GANILVTEEN KKEYVHLVCQ MRMTGAIRKQ LAAFLEGFYE
IIPKRLISIF TEQELELLIS GLPTIDIDDL KSNTEYHKYQ SNSIQIQWFW RALRSFDQAD
RAKFLQFVTG TSKVPLQGFA ALEGMNGIQK FQIHRDDRST DRLPSAHTCF NQLDLPAYES
FEKLRHMLLL AIQECSEGFG LA
