UBE4A_HUMAN
ID UBE4A_HUMAN Reviewed; 1066 AA.
AC Q14139; B0YJB6; Q2M1H0; Q6P5T4; Q7Z639;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 10-MAY-2005, sequence version 2.
DT 03-AUG-2022, entry version 177.
DE RecName: Full=Ubiquitin conjugation factor E4 A {ECO:0000305};
DE EC=2.3.2.27 {ECO:0000250|UniProtKB:E9Q735};
DE AltName: Full=RING-type E3 ubiquitin transferase E4 A;
GN Name=UBE4A {ECO:0000312|HGNC:HGNC:12499};
GN Synonyms=KIAA0126 {ECO:0000312|EMBL:BAA09475.2};
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 [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Bone marrow;
RX PubMed=8590280; DOI=10.1093/dnares/2.4.167;
RA Nagase T., Seki N., Tanaka A., Ishikawa K., Nomura N.;
RT "Prediction of the coding sequences of unidentified human genes. IV. The
RT coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by analysis of
RT cDNA clones from human cell line KG-1.";
RL DNA Res. 2:167-174(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NHLBI resequencing and genotyping service (RS&G);
RL Submitted (FEB-2007) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 PROTEIN SEQUENCE OF 545-558.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A., Thomas G.R.,
RA Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass spectrometric
RT identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [6]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-386, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA 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 [7]
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).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [9]
RP STRUCTURE BY NMR OF 977-1061.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of the U-box in human ubiquitin conjugation factor
RT E4A.";
RL Submitted (MAY-2004) to the PDB data bank.
RN [10]
RP VARIANTS NEDHMS 128-TRP--GLU-1066 DEL AND 211-ARG--GLU-1066 DEL, AND
RP INVOLVEMENT IN NEDHMS.
RX PubMed=33420346; DOI=10.1038/s41436-020-01047-z;
RA Melo U.S., Bonner D., Kent Lloyd K.C., Moshiri A., Willis B., Lanoue L.,
RA Bower L., Leonard B.C., Martins D.J., Gomes F., de Souza Leite F.,
RA Oliveira D., Kitajima J.P., Monteiro F.P., Zatz M., Menck C.F.M.,
RA Wheeler M.T., Bernstein J.A., Dumas K., Spiteri E., Di Donato N., Jahn A.,
RA Hashem M., Alsaif H.S., Chedrawi A., Alkuraya F.S., Kok F., Byers H.M.;
RT "Biallelic UBE4A loss-of-function variants cause intellectual disability
RT and global developmental delay.";
RL Genet. Med. 23:661-668(2021).
CC -!- FUNCTION: Ubiquitin-protein ligase that probably functions as an E3
CC ligase in conjunction with specific E1 and E2 ligases. May also
CC function as an E4 ligase mediating the assembly of polyubiquitin chains
CC on substrates ubiquitinated by another E3 ubiquitin ligase. Mediates
CC 'Lys-48'-linked polyubiquitination of substrates.
CC {ECO:0000250|UniProtKB:E9Q735, ECO:0000250|UniProtKB:P54860}.
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;
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000250|UniProtKB:E9Q735}.
CC -!- INTERACTION:
CC Q14139; Q92551: IP6K1; NbExp=3; IntAct=EBI-1048119, EBI-751911;
CC Q14139; Q7Z434: MAVS; NbExp=2; IntAct=EBI-1048119, EBI-995373;
CC Q14139; Q92575: UBXN4; NbExp=2; IntAct=EBI-1048119, EBI-723441;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:E9Q735}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q14139-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q14139-2; Sequence=VSP_013673;
CC -!- DOMAIN: The U-box domain is required for the ubiquitin protein ligase
CC activity. {ECO:0000250|UniProtKB:P54860, ECO:0000250|UniProtKB:Q9ES00}.
CC -!- DISEASE: Neurodevelopmental disorder with hypotonia and gross motor and
CC speech delay (NEDHMS) [MIM:619639]: An autosomal recessive disorder
CC characterized by severe global developmental delay apparent from
CC infancy, axial hypotonia, limited or absent ability to walk, impaired
CC intellectual development, and poor or absent speech. Additional
CC features may include seizures, behavioral problems, distal skeletal
CC anomalies, and facial dysmorphism. {ECO:0000269|PubMed:33420346}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- SIMILARITY: Belongs to the ubiquitin conjugation factor E4 family.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH52643.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305};
CC Sequence=AAH62695.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305};
CC Sequence=BAA09475.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; D50916; BAA09475.2; ALT_INIT; mRNA.
DR EMBL; EF445042; ACA06094.1; -; Genomic_DNA.
DR EMBL; CH471065; EAW67371.1; -; Genomic_DNA.
DR EMBL; BC052643; AAH52643.1; ALT_SEQ; mRNA.
DR EMBL; BC062695; AAH62695.1; ALT_SEQ; mRNA.
DR EMBL; BC111417; AAI11418.1; -; mRNA.
DR EMBL; BC112367; AAI12368.1; -; mRNA.
DR CCDS; CCDS55790.1; -. [Q14139-1]
DR CCDS; CCDS8396.1; -. [Q14139-2]
DR RefSeq; NP_001191006.1; NM_001204077.1. [Q14139-1]
DR RefSeq; NP_004779.2; NM_004788.3. [Q14139-2]
DR PDB; 1WGM; NMR; -; A=977-1061.
DR PDBsum; 1WGM; -.
DR AlphaFoldDB; Q14139; -.
DR SMR; Q14139; -.
DR BioGRID; 114757; 104.
DR IntAct; Q14139; 31.
DR MINT; Q14139; -.
DR STRING; 9606.ENSP00000387362; -.
DR GlyGen; Q14139; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q14139; -.
DR MetOSite; Q14139; -.
DR PhosphoSitePlus; Q14139; -.
DR BioMuta; UBE4A; -.
DR EPD; Q14139; -.
DR jPOST; Q14139; -.
DR MassIVE; Q14139; -.
DR MaxQB; Q14139; -.
DR PaxDb; Q14139; -.
DR PeptideAtlas; Q14139; -.
DR PRIDE; Q14139; -.
DR ProteomicsDB; 59840; -. [Q14139-1]
DR ProteomicsDB; 59841; -. [Q14139-2]
DR Antibodypedia; 32453; 247 antibodies from 32 providers.
DR DNASU; 9354; -.
DR Ensembl; ENST00000252108.8; ENSP00000252108.4; ENSG00000110344.10. [Q14139-1]
DR Ensembl; ENST00000431736.6; ENSP00000387362.2; ENSG00000110344.10. [Q14139-2]
DR GeneID; 9354; -.
DR KEGG; hsa:9354; -.
DR MANE-Select; ENST00000252108.8; ENSP00000252108.4; NM_001204077.2; NP_001191006.1.
DR UCSC; uc001psv.4; human. [Q14139-1]
DR CTD; 9354; -.
DR DisGeNET; 9354; -.
DR GeneCards; UBE4A; -.
DR HGNC; HGNC:12499; UBE4A.
DR HPA; ENSG00000110344; Low tissue specificity.
DR MIM; 603753; gene.
DR MIM; 619639; phenotype.
DR neXtProt; NX_Q14139; -.
DR OpenTargets; ENSG00000110344; -.
DR Orphanet; 88616; Autosomal recessive non-syndromic intellectual disability.
DR PharmGKB; PA37147; -.
DR VEuPathDB; HostDB:ENSG00000110344; -.
DR eggNOG; KOG2042; Eukaryota.
DR GeneTree; ENSGT00390000009300; -.
DR HOGENOM; CLU_003224_1_0_1; -.
DR InParanoid; Q14139; -.
DR OMA; EHDTSTQ; -.
DR OrthoDB; 194967at2759; -.
DR PhylomeDB; Q14139; -.
DR TreeFam; TF300802; -.
DR BRENDA; 2.3.2.27; 2681.
DR BRENDA; 2.3.2.B12; 2681.
DR PathwayCommons; Q14139; -.
DR Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR SignaLink; Q14139; -.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 9354; 16 hits in 1114 CRISPR screens.
DR ChiTaRS; UBE4A; human.
DR EvolutionaryTrace; Q14139; -.
DR GeneWiki; UBE4A; -.
DR GenomeRNAi; 9354; -.
DR Pharos; Q14139; Tbio.
DR PRO; PR:Q14139; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; Q14139; protein.
DR Bgee; ENSG00000110344; Expressed in endothelial cell and 213 other tissues.
DR ExpressionAtlas; Q14139; baseline and differential.
DR Genevisible; Q14139; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0000151; C:ubiquitin ligase complex; TAS:ProtInc.
DR GO; GO:0034450; F:ubiquitin-ubiquitin ligase activity; IBA:GO_Central.
DR GO; GO:0000209; P:protein polyubiquitination; IBA:GO_Central.
DR GO; GO:0030433; P:ubiquitin-dependent ERAD pathway; IBA:GO_Central.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; TAS:ProtInc.
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 3D-structure; Acetylation; Alternative splicing; Cytoplasm;
KW Direct protein sequencing; Disease variant; Intellectual disability;
KW Reference proteome; Transferase; Ubl conjugation pathway.
FT CHAIN 1..1066
FT /note="Ubiquitin conjugation factor E4 A"
FT /id="PRO_0000194990"
FT DOMAIN 987..1061
FT /note="U-box"
FT REGION 33..56
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 33..52
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 386
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT VAR_SEQ 241
FT /note="H -> REYMNKIY (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:8590280"
FT /id="VSP_013673"
FT VARIANT 128..1066
FT /note="Missing (in NEDHMS)"
FT /evidence="ECO:0000269|PubMed:33420346"
FT /id="VAR_086502"
FT VARIANT 211..1066
FT /note="Missing (in NEDHMS)"
FT /evidence="ECO:0000269|PubMed:33420346"
FT /id="VAR_086503"
FT CONFLICT 217
FT /note="P -> L (in Ref. 1; BAA09475)"
FT /evidence="ECO:0000305"
FT TURN 990..992
FT /evidence="ECO:0007829|PDB:1WGM"
FT TURN 995..997
FT /evidence="ECO:0007829|PDB:1WGM"
FT STRAND 1002..1006
FT /evidence="ECO:0007829|PDB:1WGM"
FT TURN 1008..1010
FT /evidence="ECO:0007829|PDB:1WGM"
FT STRAND 1013..1015
FT /evidence="ECO:0007829|PDB:1WGM"
FT HELIX 1016..1022
FT /evidence="ECO:0007829|PDB:1WGM"
FT TURN 1023..1025
FT /evidence="ECO:0007829|PDB:1WGM"
FT TURN 1030..1032
FT /evidence="ECO:0007829|PDB:1WGM"
FT TURN 1038..1040
FT /evidence="ECO:0007829|PDB:1WGM"
FT STRAND 1041..1043
FT /evidence="ECO:0007829|PDB:1WGM"
FT HELIX 1045..1057
FT /evidence="ECO:0007829|PDB:1WGM"
SQ SEQUENCE 1066 AA; 122561 MW; A735D670220F9DDA CRC64;
MTDQENNNNI SSNPFAALFG SLADAKQFAA IQKEQLKQQS DELPASPDDS DNSVSESLDE
FDYSVAEISR SFRSQQEICE QLNINHMIQR IFLITLDNSD PSLKSGNGIP SRCVYLEEMA
VELEDQDWLD MSNVEQALFA RLLLQDPGNH LINMTSSTTL NLSADRDAGE RHIFCYLYSC
FQRAKEEITK VPENLLPFAV QCRNLTVSNT RTVLLTPEIY VDQNIHEQLV DLMLEAIQGA
HFEDVTEFLE EVIEALILDE EVRTFPEVMI PVFDILLGRI KDLELCQILL YAYLDILLYF
TRQKDMAKVF VEYIQPKDPT NGQMYQKTLL GVILSISCLL KTPGVVENHG YFLNPSRSSP
QEIKVQEANI HQFMAQFHEK IYQMLKNLLQ LSPETKHCIL SWLGNCLHAN AGRTKIWANQ
MPEIFFQMYA SDAFFLNLGA ALLKLCQPFC KPRSSRLLTF NPTYCALKEL NDEERKIKNV
HMRGLDKETC LIPAVQEPKF PQNYNLVTEN LALTEYTLYL GFHRLHDQMV KINQNLHRLQ
VAWRDAQQSS SPAADNLREQ FERLMTIYLS TKTAMTEPQM LQNCLNLQVS MAVLLVQLAI
GNEGSQPIEL TFPLPDGYSS LAYVPEFFAD NLGDFLIFLR RFADDILETS ADSLEHVLHF
ITIFTGSIER MKNPHLRAKL AEVLEAVMPH LDQTPNPLVS SVFHRKRVFC NFQYAPQLAE
ALIKVFVDIE FTGDPHQFEQ KFNYRRPMYP ILRYMWGTDT YRESIKDLAD YASKNLEAMN
PPLFLRFLNL LMNDAIFLLD EAIQYLSKIK IQQIEKDRGE WDSLTPEARR EKEAGLQMFG
QLARFHNIMS NETIGTLAFL TSEIKSLFVH PFLAERIISM LNYFLQHLVG PKMGALKVKD
FSEFDFKPQQ LVSDICTIYL NLGDEENFCA TVPKDGRSYS PTLFAQTVRV LKKINKPGNM
IMAFSNLAER IKSLADLQQQ EEETYADACD EFLDPIMSTL MCDPVVLPSS RVTVDRSTIA
RHLLSDQTDP FNRSPLTMDQ IRPNTELKEK IQRWLAERKQ QKEQLE
