ID   HERC4_HUMAN             Reviewed;        1057 AA.
AC   Q5GLZ8; Q5GC98; Q5GC99; Q5GCA0; Q8IXP9; Q9HCH9;
DT   20-FEB-2007, integrated into UniProtKB/Swiss-Prot.
DT   01-MAR-2005, sequence version 1.
DT   27-MAR-2024, entry version 152.
DE   RecName: Full=Probable E3 ubiquitin-protein ligase HERC4;
DE            EC=2.3.2.26;
DE   AltName: Full=HECT domain and RCC1-like domain-containing protein 4;
DE   AltName: Full=HECT-type E3 ubiquitin transferase HERC4;
GN   Name=HERC4; Synonyms=KIAA1593;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 3; 4 AND 5), TISSUE SPECIFICITY,
RP   DEVELOPMENTAL STAGE, AND SUBCELLULAR LOCATION.
RC   TISSUE=Cervix carcinoma;
RX   PubMed=15676274; DOI=10.1016/j.ygeno.2004.10.006;
RA   Hochrainer K., Mayer H., Baranyi U., Binder B.R., Lipp J., Kroismayr R.;
RT   "The human HERC family of ubiquitin ligases: novel members, genomic
RT   organization, expression profiling, and evolutionary aspects.";
RL   Genomics 85:153-164(2005).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 6).
RC   TISSUE=Brain;
RX   PubMed=10997877; DOI=10.1093/dnares/7.4.271;
RA   Nagase T., Kikuno R., Nakayama M., Hirosawa M., Ohara O.;
RT   "Prediction of the coding sequences of unidentified human genes. XVIII. The
RT   complete sequences of 100 new cDNA clones from brain which code for large
RT   proteins in vitro.";
RL   DNA Res. 7:273-281(2000).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15164054; DOI=10.1038/nature02462;
RA   Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA   Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA   Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA   Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA   Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA   Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y.,
RA   Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P.,
RA   Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N.,
RA   Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A.,
RA   Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C.,
RA   Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D.,
RA   Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C.,
RA   Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K.,
RA   Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A.,
RA   Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S.,
RA   McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S.,
RA   Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V.,
RA   Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A.,
RA   Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA   Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A.,
RA   Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P.,
RA   Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y.,
RA   Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D.,
RA   Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT   "The DNA sequence and comparative analysis of human chromosome 10.";
RL   Nature 429:375-381(2004).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC   TISSUE=Blood;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [5]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA   Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
CC   -!- FUNCTION: Probable E3 ubiquitin-protein ligase involved in either
CC       protein trafficking or in the distribution of cellular structures.
CC       Required for spermatozoon maturation and fertility, and for the removal
CC       of the cytoplasmic droplet of the spermatozoon. E3 ubiquitin-protein
CC       ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the
CC       form of a thioester and then directly transfer it to targeted
CC       substrates. {ECO:0000250|UniProtKB:Q6PAV2}.
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;
CC   -!- PATHWAY: Protein modification; protein ubiquitination.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:15676274}.
CC       Note=shows a punctate cytoplasmic distribution.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=6;
CC       Name=1;
CC         IsoId=Q5GLZ8-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q5GLZ8-2; Sequence=VSP_023178;
CC       Name=3;
CC         IsoId=Q5GLZ8-3; Sequence=VSP_023179;
CC       Name=4;
CC         IsoId=Q5GLZ8-4; Sequence=VSP_023174, VSP_023175;
CC       Name=5; Synonyms=2;
CC         IsoId=Q5GLZ8-5; Sequence=VSP_023173, VSP_023176;
CC       Name=6;
CC         IsoId=Q5GLZ8-6; Sequence=VSP_023172, VSP_039551;
CC   -!- TISSUE SPECIFICITY: Expressed in brain and testis and detected in heart
CC       and placenta. {ECO:0000269|PubMed:15676274}.
CC   -!- DEVELOPMENTAL STAGE: Expressed in fetal brain.
CC       {ECO:0000269|PubMed:15676274}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=BAB13419.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR   EMBL; AY221963; AAO65480.1; -; mRNA.
DR   EMBL; AY650032; AAV66578.1; -; mRNA.
DR   EMBL; AY650033; AAV66579.1; -; mRNA.
DR   EMBL; AY650034; AAV66580.1; -; mRNA.
DR   EMBL; AB046813; BAB13419.1; ALT_INIT; mRNA.
DR   EMBL; AC024258; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AL133551; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AL356741; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC039600; AAH39600.1; -; mRNA.
DR   CCDS; CCDS41533.1; -. [Q5GLZ8-1]
DR   CCDS; CCDS60541.1; -. [Q5GLZ8-3]
DR   CCDS; CCDS60542.1; -. [Q5GLZ8-4]
DR   CCDS; CCDS7274.1; -. [Q5GLZ8-2]
DR   RefSeq; NP_001265114.1; NM_001278185.1. [Q5GLZ8-3]
DR   RefSeq; NP_001265115.1; NM_001278186.1.
DR   RefSeq; NP_001265116.1; NM_001278187.1. [Q5GLZ8-4]
DR   RefSeq; NP_056416.2; NM_015601.3. [Q5GLZ8-2]
DR   RefSeq; NP_071362.1; NM_022079.2. [Q5GLZ8-1]
DR   AlphaFoldDB; Q5GLZ8; -.
DR   SMR; Q5GLZ8; -.
DR   BioGRID; 117542; 86.
DR   IntAct; Q5GLZ8; 20.
DR   STRING; 9606.ENSP00000378624; -.
DR   GlyGen; Q5GLZ8; 1 site, 1 O-linked glycan (1 site).
DR   iPTMnet; Q5GLZ8; -.
DR   MetOSite; Q5GLZ8; -.
DR   PhosphoSitePlus; Q5GLZ8; -.
DR   SwissPalm; Q5GLZ8; -.
DR   BioMuta; HERC4; -.
DR   DMDM; 74707832; -.
DR   EPD; Q5GLZ8; -.
DR   jPOST; Q5GLZ8; -.
DR   MassIVE; Q5GLZ8; -.
DR   MaxQB; Q5GLZ8; -.
DR   PaxDb; 9606-ENSP00000378624; -.
DR   PeptideAtlas; Q5GLZ8; -.
DR   ProteomicsDB; 62837; -. [Q5GLZ8-1]
DR   ProteomicsDB; 62838; -. [Q5GLZ8-2]
DR   ProteomicsDB; 62839; -. [Q5GLZ8-3]
DR   ProteomicsDB; 62840; -. [Q5GLZ8-4]
DR   ProteomicsDB; 62841; -. [Q5GLZ8-5]
DR   ProteomicsDB; 62842; -. [Q5GLZ8-6]
DR   Pumba; Q5GLZ8; -.
DR   Antibodypedia; 28396; 197 antibodies from 27 providers.
DR   DNASU; 26091; -.
DR   Ensembl; ENST00000277817.10; ENSP00000277817.6; ENSG00000148634.16. [Q5GLZ8-6]
DR   Ensembl; ENST00000373700.9; ENSP00000362804.4; ENSG00000148634.16. [Q5GLZ8-2]
DR   Ensembl; ENST00000395198.7; ENSP00000378624.3; ENSG00000148634.16. [Q5GLZ8-1]
DR   Ensembl; ENST00000412272.6; ENSP00000416504.2; ENSG00000148634.16. [Q5GLZ8-3]
DR   Ensembl; ENST00000473533.6; ENSP00000423671.1; ENSG00000148634.16. [Q5GLZ8-5]
DR   Ensembl; ENST00000492996.6; ENSP00000422383.1; ENSG00000148634.16. [Q5GLZ8-4]
DR   GeneID; 26091; -.
DR   KEGG; hsa:26091; -.
DR   MANE-Select; ENST00000373700.9; ENSP00000362804.4; NM_015601.4; NP_056416.2. [Q5GLZ8-2]
DR   UCSC; uc001jng.5; human. [Q5GLZ8-1]
DR   AGR; HGNC:24521; -.
DR   CTD; 26091; -.
DR   DisGeNET; 26091; -.
DR   GeneCards; HERC4; -.
DR   HGNC; HGNC:24521; HERC4.
DR   HPA; ENSG00000148634; Low tissue specificity.
DR   MIM; 609248; gene.
DR   neXtProt; NX_Q5GLZ8; -.
DR   OpenTargets; ENSG00000148634; -.
DR   PharmGKB; PA134949021; -.
DR   VEuPathDB; HostDB:ENSG00000148634; -.
DR   eggNOG; KOG0941; Eukaryota.
DR   GeneTree; ENSGT00940000158924; -.
DR   HOGENOM; CLU_2084036_0_0_1; -.
DR   InParanoid; Q5GLZ8; -.
DR   OMA; FKSQACW; -.
DR   OrthoDB; 5475808at2759; -.
DR   PhylomeDB; Q5GLZ8; -.
DR   TreeFam; TF315189; -.
DR   PathwayCommons; Q5GLZ8; -.
DR   Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR   SignaLink; Q5GLZ8; -.
DR   SIGNOR; Q5GLZ8; -.
DR   UniPathway; UPA00143; -.
DR   BioGRID-ORCS; 26091; 12 hits in 1201 CRISPR screens.
DR   ChiTaRS; HERC4; human.
DR   GenomeRNAi; 26091; -.
DR   Pharos; Q5GLZ8; Tbio.
DR   PRO; PR:Q5GLZ8; -.
DR   Proteomes; UP000005640; Chromosome 10.
DR   RNAct; Q5GLZ8; Protein.
DR   Bgee; ENSG00000148634; Expressed in adrenal tissue and 185 other cell types or tissues.
DR   ExpressionAtlas; Q5GLZ8; baseline and differential.
DR   Genevisible; Q5GLZ8; HS.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0005829; C:cytosol; IDA:HPA.
DR   GO; GO:0001650; C:fibrillar center; IDA:HPA.
DR   GO; GO:0061630; F:ubiquitin protein ligase activity; IBA:GO_Central.
DR   GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR   GO; GO:0045879; P:negative regulation of smoothened signaling pathway; IMP:FlyBase.
DR   GO; GO:0016567; P:protein ubiquitination; IBA:GO_Central.
DR   GO; GO:0007283; P:spermatogenesis; ISS:UniProtKB.
DR   GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IBA:GO_Central.
DR   CDD; cd00078; HECTc; 1.
DR   Gene3D; 3.30.2160.10; Hect, E3 ligase catalytic domain; 1.
DR   Gene3D; 3.30.2410.10; Hect, E3 ligase catalytic domain; 1.
DR   Gene3D; 3.90.1750.10; Hect, E3 ligase catalytic domains; 1.
DR   Gene3D; 2.130.10.30; Regulator of chromosome condensation 1/beta-lactamase-inhibitor protein II; 2.
DR   InterPro; IPR000569; HECT_dom.
DR   InterPro; IPR035983; Hect_E3_ubiquitin_ligase.
DR   InterPro; IPR009091; RCC1/BLIP-II.
DR   InterPro; IPR000408; Reg_chr_condens.
DR   PANTHER; PTHR45622:SF5; E3 UBIQUITIN-PROTEIN LIGASE HERC4-RELATED; 1.
DR   PANTHER; PTHR45622; UBIQUITIN-PROTEIN LIGASE E3A-RELATED; 1.
DR   Pfam; PF00632; HECT; 1.
DR   Pfam; PF00415; RCC1; 7.
DR   PRINTS; PR00633; RCCNDNSATION.
DR   SMART; SM00119; HECTc; 1.
DR   SUPFAM; SSF56204; Hect, E3 ligase catalytic domain; 1.
DR   SUPFAM; SSF50985; RCC1/BLIP-II; 1.
DR   PROSITE; PS50237; HECT; 1.
DR   PROSITE; PS00626; RCC1_2; 3.
DR   PROSITE; PS50012; RCC1_3; 7.
PE   1: Evidence at protein level;
KW   Alternative splicing; Cytoplasm; Differentiation; Reference proteome;
KW   Repeat; Spermatogenesis; Transferase; Ubl conjugation pathway.
FT   CHAIN           1..1057
FT                   /note="Probable E3 ubiquitin-protein ligase HERC4"
FT                   /id="PRO_0000278216"
FT   REPEAT          1..51
FT                   /note="RCC1 1"
FT   REPEAT          52..101
FT                   /note="RCC1 2"
FT   REPEAT          102..154
FT                   /note="RCC1 3"
FT   REPEAT          156..207
FT                   /note="RCC1 4"
FT   REPEAT          208..259
FT                   /note="RCC1 5"
FT   REPEAT          261..311
FT                   /note="RCC1 6"
FT   REPEAT          313..368
FT                   /note="RCC1 7"
FT   DOMAIN          730..1057
FT                   /note="HECT"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00104"
FT   ACT_SITE        1025
FT                   /note="Glycyl thioester intermediate"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00104"
FT   VAR_SEQ         1..110
FT                   /note="Missing (in isoform 6)"
FT                   /evidence="ECO:0000303|PubMed:10997877"
FT                   /id="VSP_023172"
FT   VAR_SEQ         77..117
FT                   /note="QVVALDAQNIVAVSCGEAHTLALNDKGQVYAWGLDSDGQLG -> ILKVCQI
FT                   SRLYRLLVVTIIHLHFLKQVKSSVGDRINMANWV (in isoform 5)"
FT                   /evidence="ECO:0000303|PubMed:15489334,
FT                   ECO:0000303|PubMed:15676274"
FT                   /id="VSP_023173"
FT   VAR_SEQ         77..110
FT                   /note="QVVALDAQNIVAVSCGEAHTLALNDKGQVYAWGL -> FRSCFPGRSAMAPS
FT                   RLTATSASQVQAILLPQPPE (in isoform 4)"
FT                   /evidence="ECO:0000303|PubMed:15676274"
FT                   /id="VSP_023174"
FT   VAR_SEQ         111..1057
FT                   /note="Missing (in isoform 4)"
FT                   /evidence="ECO:0000303|PubMed:15676274"
FT                   /id="VSP_023175"
FT   VAR_SEQ         111..128
FT                   /note="DSDGQLGLVGSEECIRVP -> MCVDSLVRICSGLSYGRI (in isoform
FT                   6)"
FT                   /evidence="ECO:0000303|PubMed:10997877"
FT                   /id="VSP_039551"
FT   VAR_SEQ         118..1057
FT                   /note="Missing (in isoform 5)"
FT                   /evidence="ECO:0000303|PubMed:15489334,
FT                   ECO:0000303|PubMed:15676274"
FT                   /id="VSP_023176"
FT   VAR_SEQ         643..650
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_023178"
FT   VAR_SEQ         788..865
FT                   /note="Missing (in isoform 3)"
FT                   /evidence="ECO:0000303|PubMed:15676274"
FT                   /id="VSP_023179"
FT   CONFLICT        1032
FT                   /note="P -> S (in Ref. 1; AAV66579)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   1057 AA;  118563 MW;  7F06DA755A68243A CRC64;
     MLCWGNASFG QLGLGGIDEE IVLEPRKSDF FINKRVRDVG CGLRHTVFVL DDGTVYTCGC
     NDLGQLGHEK SRKKPEQVVA LDAQNIVAVS CGEAHTLALN DKGQVYAWGL DSDGQLGLVG
     SEECIRVPRN IKSLSDIQIV QVACGYYHSL ALSKASEVFC WGQNKYGQLG LGTDCKKQTS
     PQLLKSLLGI PFMQVAAGGA HSFVLTLSGA IFGWGRNKFG QLGLNDENDR YVPNLLKSLR
     SQKIVYICCG EDHTAALTKE GGVFTFGAGG YGQLGHNSTS HEINPRKVFE LMGSIVTEIA
     CGRQHTSAFV PSSGRIYSFG LGGNGQLGTG STSNRKSPFT VKGNWYPYNG QCLPDIDSEE
     YFCVKRIFSG GDQSFSHYSS PQNCGPPDDF RCPNPTKQIW TVNEALIQKW LSYPSGRFPV
     EIANEIDGTF SSSGCLNGSF LAVSNDDHYR TGTRFSGVDM NAARLLFHKL IQPDHPQISQ
     QVAASLEKNL IPKLTSSLPD VEALRFYLTL PECPLMSDSN NFTTIAIPFG TALVNLEKAP
     LKVLENWWSV LEPPLFLKIV ELFKEVVVHL LKLYKIGIPP SERRIFNSFL HTALKVLEIL
     HRVNEKMGQI IQYDKFYIHE VQELIDIRND YINWVQQQAY GMDVNHGLTE LADIPVTICT
     YPFVFDAQAK TTLLQTDAVL QMQMAIDQAH RQNVSSLFLP VIESVNPCLI LVVRRENIVG
     DAMEVLRKTK NIDYKKPLKV IFVGEDAVDA GGVRKEFFLL IMRELLDPKY GMFRYYEDSR
     LIWFSDKTFE DSDLFHLIGV ICGLAIYNCT IVDLHFPLAL YKKLLKKKPS LDDLKELMPD
     VGRSMQQLLD YPEDDIEETF CLNFTITVEN FGATEVKELV LNGADTAVNK QNRQEFVDAY
     VDYIFNKSVA SLFDAFHAGF HKVCGGKVLL LFQPNELQAM VIGNTNYDWK ELEKNTEYKG
     EYWAEHPTIK IFWEVFHELP LEKKKQFLLF LTGSDRIPIL GMKSLKLVIQ STGGGEEYLP
     VSHTCFNLLD LPKYTEKETL RSKLIQAIDH NEGFSLI
//