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Protein

Ubiquitin carboxyl-terminal hydrolase 4

Gene

USP4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Hydrolase that deubiquitinates target proteins such as the receptor ADORA2A, PDPK1 and TRIM21. Deubiquitination of ADORA2A increases the amount of functional receptor at the cell surface. May regulate mRNA splicing through deubiquitination of the U4 spliceosomal protein PRPF3. This may prevent its recognition by the U5 component PRPF8 thereby destabilizing interactions within the U4/U6.U5 snRNP. May also play a role in the regulation of quality control in the ER.5 Publications

Catalytic activityi

Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal).

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei311Nucleophile1
Metal bindingi461Zinc1
Metal bindingi464Zinc1
Metal bindingi799Zinc1
Metal bindingi802Zinc1
Active sitei881Proton acceptorPROSITE-ProRule annotation1

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionHydrolase, Protease, Thiol protease
Biological processUbl conjugation pathway
LigandMetal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-HSA-5357786 TNFR1-induced proapoptotic signaling
R-HSA-5357905 Regulation of TNFR1 signaling
R-HSA-5357956 TNFR1-induced NFkappaB signaling pathway
R-HSA-5689880 Ub-specific processing proteases

Protein family/group databases

MEROPSiC19.010

Names & Taxonomyi

Protein namesi
Recommended name:
Ubiquitin carboxyl-terminal hydrolase 4 (EC:3.4.19.12)
Alternative name(s):
Deubiquitinating enzyme 4
Ubiquitin thioesterase 4
Ubiquitin-specific-processing protease 4
Ubiquitous nuclear protein homolog
Gene namesi
Name:USP4
Synonyms:UNP, UNPH
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 3

Organism-specific databases

EuPathDBiHostDB:ENSG00000114316.12
HGNCiHGNC:12627 USP4
MIMi603486 gene
neXtProtiNX_Q13107

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi311C → A: Loss of activity. Its ubiquitination by TRIM21 is enhanced. 2 Publications1
Mutagenesisi459 – 463LVCPE → AVRPH: Reduces the interaction with RB1. 1 Publication5
Mutagenesisi463E → Q: Reduces the interaction with RB1. 1 Publication1

Keywords - Diseasei

Proto-oncogene

Organism-specific databases

DisGeNETi7375
OpenTargetsiENSG00000114316
PharmGKBiPA37252

Chemistry databases

ChEMBLiCHEMBL2406900

Polymorphism and mutation databases

BioMutaiUSP4
DMDMi116242839

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000806211 – 963Ubiquitin carboxyl-terminal hydrolase 4Add BLAST963

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei655PhosphoserineBy similarity1
Modified residuei675PhosphoserineBy similarity1
Modified residuei680PhosphoserineBy similarity1

Post-translational modificationi

Monoubiquitinated by TRIM21. Ubiquitination does not lead to its proteasomal degradation. Autodeubiquitinated.2 Publications

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ13107
MaxQBiQ13107
PaxDbiQ13107
PeptideAtlasiQ13107
PRIDEiQ13107
ProteomicsDBi59158
59159 [Q13107-2]

PTM databases

iPTMnetiQ13107
PhosphoSitePlusiQ13107

Expressioni

Tissue specificityi

Overexpressed in small cell tumors and adenocarcinomas of the lung compared to wild-type lung (at protein level). Expressed in the hippocampal neurons.2 Publications

Gene expression databases

BgeeiENSG00000114316 Expressed in 225 organ(s), highest expression level in testis
CleanExiHS_USP4
ExpressionAtlasiQ13107 baseline and differential
GenevisibleiQ13107 HS

Organism-specific databases

HPAiHPA018499

Interactioni

Subunit structurei

Interacts with RB1 (both dephosphorylated and hypophosphorylated forms). Interacts with RBL1 and RBL2. Interacts with ADORA2A (via cytoplasmic C-terminus); the interaction is direct. Interacts with SART3; recruits USP4 to its substrate PRPF3.By similarity3 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi113221, 116 interactors
IntActiQ13107, 32 interactors
MINTiQ13107
STRINGi9606.ENSP00000265560

Chemistry databases

BindingDBiQ13107

Structurei

Secondary structure

1963
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliQ13107
SMRiQ13107
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ13107

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini11 – 122DUSPPROSITE-ProRule annotationAdd BLAST112
Domaini142 – 226Ubiquitin-like 1Add BLAST85
Domaini302 – 923USPAdd BLAST622
Domaini483 – 571Ubiquitin-like 2Add BLAST89

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni27 – 216Necessary for interaction with SART31 PublicationAdd BLAST190
Regioni405 – 407Necessary for interaction with RBL2By similarity3
Regioni459 – 463Necessary for interaction with RB1 and RBL2By similarity5

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi133 – 141Nuclear export signalBy similarity9
Motifi767 – 772Nuclear localization signalBy similarity6

Domaini

The Ubiquitin-like domain 2 inserts into the catalytic domain and competes with the ubiquitin substrate, partially inhibiting DUB activity.1 Publication

Sequence similaritiesi

Belongs to the peptidase C19 family. USP4 subfamily.Curated

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG1870 Eukaryota
COG5560 LUCA
GeneTreeiENSGT00670000097750
HOGENOMiHOG000264375
HOVERGENiHBG000864
InParanoidiQ13107
KOiK11835
OMAiHVSMLQP
OrthoDBiEOG091G0157
PhylomeDBiQ13107
TreeFamiTF106276

Family and domain databases

InterProiView protein in InterPro
IPR035927 DUSP-like_sf
IPR038765 Papain_like_cys_pep_sf
IPR006615 Pept_C19_DUSP
IPR001394 Peptidase_C19_UCH
IPR028135 Ub_USP-typ
IPR028134 USP4
IPR018200 USP_CS
IPR028889 USP_dom
PANTHERiPTHR43913 PTHR43913, 1 hit
PfamiView protein in Pfam
PF06337 DUSP, 1 hit
PF14836 Ubiquitin_3, 1 hit
PF00443 UCH, 1 hit
SMARTiView protein in SMART
SM00695 DUSP, 1 hit
SUPFAMiSSF143791 SSF143791, 1 hit
SSF54001 SSF54001, 2 hits
PROSITEiView protein in PROSITE
PS51283 DUSP, 1 hit
PS00972 USP_1, 1 hit
PS00973 USP_2, 1 hit
PS50235 USP_3, 1 hit

Sequences (3+)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

This entry has 3 described isoforms and 2 potential isoforms that are computationally mapped.Show allAlign All

Isoform 1 (identifier: Q13107-1) [UniParc]FASTAAdd to basket
Also known as: UnpEL

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide
        10         20         30         40         50
MAEGGGCRER PDAETQKSEL GPLMRTTLQR GAQWYLIDSR WFKQWKKYVG
60 70 80 90 100
FDSWDMYNVG EHNLFPGPID NSGLFSDPES QTLKEHLIDE LDYVLVPTEA
110 120 130 140 150
WNKLLNWYGC VEGQQPIVRK VVEHGLFVKH CKVEVYLLEL KLCENSDPTN
160 170 180 190 200
VLSCHFSKAD TIATIEKEMR KLFNIPAERE TRLWNKYMSN TYEQLSKLDN
210 220 230 240 250
TVQDAGLYQG QVLVIEPQNE DGTWPRQTLQ SKSSTAPSRN FTTSPKSSAS
260 270 280 290 300
PYSSVSASLI ANGDSTSTCG MHSSGVSRGG SGFSASYNCQ EPPSSHIQPG
310 320 330 340 350
LCGLGNLGNT CFMNSALQCL SNTAPLTDYF LKDEYEAEIN RDNPLGMKGE
360 370 380 390 400
IAEAYAELIK QMWSGRDAHV APRMFKTQVG RFAPQFSGYQ QQDSQELLAF
410 420 430 440 450
LLDGLHEDLN RVKKKPYLEL KDANGRPDAV VAKEAWENHR LRNDSVIVDT
460 470 480 490 500
FHGLFKSTLV CPECAKVSVT FDPFCYLTLP LPLKKDRVME VFLVPADPHC
510 520 530 540 550
RPTQYRVTVP LMGAVSDLCE ALSRLSGIAA ENMVVADVYN HRFHKIFQMD
560 570 580 590 600
EGLNHIMPRD DIFVYEVCST SVDGSECVTL PVYFRERKSR PSSTSSASAL
610 620 630 640 650
YGQPLLLSVP KHKLTLESLY QAVCDRISRY VKQPLPDEFG SSPLEPGACN
660 670 680 690 700
GSRNSCEGED EEEMEHQEEG KEQLSETEGS GEDEPGNDPS ETTQKKIKGQ
710 720 730 740 750
PCPKRLFTFS LVNSYGTADI NSLAADGKLL KLNSRSTLAM DWDSETRRLY
760 770 780 790 800
YDEQESEAYE KHVSMLQPQK KKKTTVALRD CIELFTTMET LGEHDPWYCP
810 820 830 840 850
NCKKHQQATK KFDLWSLPKI LVVHLKRFSY NRYWRDKLDT VVEFPIRGLN
860 870 880 890 900
MSEFVCNLSA RPYVYDLIAV SNHYGAMGVG HYTAYAKNKL NGKWYYFDDS
910 920 930 940 950
NVSLASEDQI VTKAAYVLFY QRRDDEFYKT PSLSSSGSSD GGTRPSSSQQ
960
GFGDDEACSM DTN
Length:963
Mass (Da):108,565
Last modified:October 17, 2006 - v3
Checksum:i63055C9ADFE36713
GO
Isoform 2 (identifier: Q13107-2) [UniParc]FASTAAdd to basket
Also known as: UnpES

The sequence of this isoform differs from the canonical sequence as follows:
     232-279: KSSTAPSRNFTTSPKSSASPYSSVSASLIANGDSTSTCGMHSSGVSRG → N

Show »
Length:916
Mass (Da):103,958
Checksum:i86CBBDE6AA2AB04E
GO
Isoform 3 (identifier: Q13107-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     233-313: SSTAPSRNFT...LGNLGNTCFM → VSFFLPRLEC...LLPQPPEWLG
     314-963: Missing.

Note: No experimental confirmation available.
Show »
Length:313
Mass (Da):35,661
Checksum:i7B2258A3A64AC0EB
GO

Computationally mapped potential isoform sequencesi

There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
H7C189H7C189_HUMAN
Ubiquitin carboxyl-terminal hydrola...
USP4
621Annotation score:
C9JNU9C9JNU9_HUMAN
Ubiquitin carboxyl-terminal hydrola...
USP4
363Annotation score:

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti373R → S in AAB72237 (PubMed:7784062).Curated1
Sequence conflicti744S → R in AAB72237 (PubMed:7784062).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_028180620Y → C. Corresponds to variant dbSNP:rs9311440Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_005258232 – 279KSSTA…GVSRG → N in isoform 2. 1 PublicationAdd BLAST48
Alternative sequenceiVSP_044814233 – 313SSTAP…NTCFM → VSFFLPRLECNGAILAHCNF CLPGSSNSPASASRVAPSHL ANFFFFEMESHSVTKLECGG AVSAYSRVQVMLLPQPPEWL G in isoform 3. 1 PublicationAdd BLAST81
Alternative sequenceiVSP_044815314 – 963Missing in isoform 3. 1 PublicationAdd BLAST650

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U20657 mRNA Translation: AAB72237.1
AF017305 mRNA Translation: AAC27355.1
AF017306 mRNA Translation: AAC27356.1
AK291795 mRNA Translation: BAF84484.1
AC121247 Genomic DNA No translation available.
BC068017 mRNA No translation available.
BC125130 mRNA Translation: AAI25131.1
CCDSiCCDS2793.1 [Q13107-1]
CCDS2794.1 [Q13107-2]
CCDS58832.1 [Q13107-3]
PIRiT09478
RefSeqiNP_001238806.1, NM_001251877.1 [Q13107-3]
NP_003354.2, NM_003363.3 [Q13107-1]
NP_955475.1, NM_199443.2 [Q13107-2]
UniGeneiHs.403828
Hs.77500

Genome annotation databases

EnsembliENST00000265560; ENSP00000265560; ENSG00000114316 [Q13107-1]
ENST00000351842; ENSP00000341028; ENSG00000114316 [Q13107-2]
ENST00000416417; ENSP00000400623; ENSG00000114316 [Q13107-3]
GeneIDi7375
KEGGihsa:7375
UCSCiuc003cwq.3 human [Q13107-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U20657 mRNA Translation: AAB72237.1
AF017305 mRNA Translation: AAC27355.1
AF017306 mRNA Translation: AAC27356.1
AK291795 mRNA Translation: BAF84484.1
AC121247 Genomic DNA No translation available.
BC068017 mRNA No translation available.
BC125130 mRNA Translation: AAI25131.1
CCDSiCCDS2793.1 [Q13107-1]
CCDS2794.1 [Q13107-2]
CCDS58832.1 [Q13107-3]
PIRiT09478
RefSeqiNP_001238806.1, NM_001251877.1 [Q13107-3]
NP_003354.2, NM_003363.3 [Q13107-1]
NP_955475.1, NM_199443.2 [Q13107-2]
UniGeneiHs.403828
Hs.77500

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2Y6EX-ray2.40A/B/C/D/E/F296-490[»]
A/B/C/D/E/F765-932[»]
5CTRX-ray3.01C/D1-230[»]
ProteinModelPortaliQ13107
SMRiQ13107
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi113221, 116 interactors
IntActiQ13107, 32 interactors
MINTiQ13107
STRINGi9606.ENSP00000265560

Chemistry databases

BindingDBiQ13107
ChEMBLiCHEMBL2406900

Protein family/group databases

MEROPSiC19.010

PTM databases

iPTMnetiQ13107
PhosphoSitePlusiQ13107

Polymorphism and mutation databases

BioMutaiUSP4
DMDMi116242839

Proteomic databases

EPDiQ13107
MaxQBiQ13107
PaxDbiQ13107
PeptideAtlasiQ13107
PRIDEiQ13107
ProteomicsDBi59158
59159 [Q13107-2]

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000265560; ENSP00000265560; ENSG00000114316 [Q13107-1]
ENST00000351842; ENSP00000341028; ENSG00000114316 [Q13107-2]
ENST00000416417; ENSP00000400623; ENSG00000114316 [Q13107-3]
GeneIDi7375
KEGGihsa:7375
UCSCiuc003cwq.3 human [Q13107-1]

Organism-specific databases

CTDi7375
DisGeNETi7375
EuPathDBiHostDB:ENSG00000114316.12
GeneCardsiUSP4
HGNCiHGNC:12627 USP4
HPAiHPA018499
MIMi603486 gene
neXtProtiNX_Q13107
OpenTargetsiENSG00000114316
PharmGKBiPA37252
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG1870 Eukaryota
COG5560 LUCA
GeneTreeiENSGT00670000097750
HOGENOMiHOG000264375
HOVERGENiHBG000864
InParanoidiQ13107
KOiK11835
OMAiHVSMLQP
OrthoDBiEOG091G0157
PhylomeDBiQ13107
TreeFamiTF106276

Enzyme and pathway databases

ReactomeiR-HSA-5357786 TNFR1-induced proapoptotic signaling
R-HSA-5357905 Regulation of TNFR1 signaling
R-HSA-5357956 TNFR1-induced NFkappaB signaling pathway
R-HSA-5689880 Ub-specific processing proteases

Miscellaneous databases

ChiTaRSiUSP4 human
EvolutionaryTraceiQ13107
GeneWikiiUSP4
GenomeRNAii7375
PROiPR:Q13107
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000114316 Expressed in 225 organ(s), highest expression level in testis
CleanExiHS_USP4
ExpressionAtlasiQ13107 baseline and differential
GenevisibleiQ13107 HS

Family and domain databases

InterProiView protein in InterPro
IPR035927 DUSP-like_sf
IPR038765 Papain_like_cys_pep_sf
IPR006615 Pept_C19_DUSP
IPR001394 Peptidase_C19_UCH
IPR028135 Ub_USP-typ
IPR028134 USP4
IPR018200 USP_CS
IPR028889 USP_dom
PANTHERiPTHR43913 PTHR43913, 1 hit
PfamiView protein in Pfam
PF06337 DUSP, 1 hit
PF14836 Ubiquitin_3, 1 hit
PF00443 UCH, 1 hit
SMARTiView protein in SMART
SM00695 DUSP, 1 hit
SUPFAMiSSF143791 SSF143791, 1 hit
SSF54001 SSF54001, 2 hits
PROSITEiView protein in PROSITE
PS51283 DUSP, 1 hit
PS00972 USP_1, 1 hit
PS00973 USP_2, 1 hit
PS50235 USP_3, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiUBP4_HUMAN
AccessioniPrimary (citable) accession number: Q13107
Secondary accession number(s): A8K6Y0
, C9IY91, O43452, O43453, Q08AK8
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: October 17, 2006
Last modified: October 10, 2018
This is version 175 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 3
    Human chromosome 3: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Peptidase families
    Classification of peptidase families and list of entries
  4. SIMILARITY comments
    Index of protein domains and families
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  7. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
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