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Protein

Ubiquitin carboxyl-terminal hydrolase 25

Gene

USP25

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Deubiquitinating enzyme that hydrolyzes ubiquitin moieties conjugated to substrates and thus, functions to process newly synthesized Ubiquitin, to recycle ubiquitin molecules or to edit polyubiquitin chains and prevents proteasomal degradation of substrates. Hydrolyzes both 'Lys-48'- and 'Lys-63'-linked tetraubiquitin chains.
The muscle-specific isoform (USP25m) may have a role in the regulation of muscular differentiation and function.

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 sitei1781 Publication1
Active sitei599By similarity1
Active sitei607By similarity1

GO - Molecular functioni

  • ATPase binding Source: ParkinsonsUK-UCL
  • peptidase activity Source: ProtInc
  • SUMO binding Source: UniProtKB
  • thiol-dependent ubiquitin-specific protease activity Source: UniProtKB
  • ubiquitin binding Source: ParkinsonsUK-UCL
  • ubiquitin protein ligase binding Source: ParkinsonsUK-UCL
  • ubiquitin-specific protease activity involved in negative regulation of ERAD pathway Source: ParkinsonsUK-UCL

GO - Biological processi

  • cellular protein modification process Source: ProtInc
  • negative regulation of ERAD pathway Source: ParkinsonsUK-UCL
  • protein deubiquitination Source: ParkinsonsUK-UCL
  • protein K48-linked deubiquitination Source: UniProtKB
  • protein K63-linked deubiquitination Source: UniProtKB
  • proteolysis Source: ProtInc
  • ubiquitin-dependent protein catabolic process Source: InterPro
Complete GO annotation...

Keywords - Molecular functioni

Hydrolase, Protease, Thiol protease

Keywords - Biological processi

Ubl conjugation pathway

Enzyme and pathway databases

BioCyciZFISH:HS08041-MONOMER.
ReactomeiR-HSA-5689880. Ub-specific processing proteases.

Protein family/group databases

MEROPSiC19.041.

Names & Taxonomyi

Protein namesi
Recommended name:
Ubiquitin carboxyl-terminal hydrolase 25 (EC:3.4.19.12)
Alternative name(s):
Deubiquitinating enzyme 25
USP on chromosome 21
Ubiquitin thioesterase 25
Ubiquitin-specific-processing protease 25
Gene namesi
Name:USP25
Synonyms:USP21
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 21

Organism-specific databases

HGNCiHGNC:12624. USP25.

Subcellular locationi

Isoform USP25m :
  • Cytoplasm By similarity
  • Nucleus By similarity

  • Note: Some transient punctuate nuclear location in myotubes during myocyte development.By similarity

GO - Cellular componenti

  • cytoplasm Source: HPA
  • endoplasmic reticulum Source: ParkinsonsUK-UCL
  • nucleus Source: UniProtKB-SubCell
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi91V → A: No interaction with SUMO3; when associated with A-92. 1 Publication1
Mutagenesisi92I → A: No interaction with SUMO3; when associated with A-91. 1 Publication1
Mutagenesisi99K → R: Abolishes sumoylation. Decreased enzymatic activity. 2 Publications1
Mutagenesisi178C → S: Abrogates deubiquitinating activity. No effect on homo- or oligomerization. 1 Publication1
Mutagenesisi740Y → F: No effect on interaction with SYK. 1 Publication1
Mutagenesisi878T → I: No effect on interaction with SYK. 1 Publication1
Mutagenesisi880Y → F: No effect on interaction with SYK. 1 Publication1
Mutagenesisi883I → S: No effect on interaction with SYK. 1 Publication1

Organism-specific databases

DisGeNETi29761.
OpenTargetsiENSG00000155313.
PharmGKBiPA37249.

Polymorphism and mutation databases

DMDMi302393833.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000806531 – 1055Ubiquitin carboxyl-terminal hydrolase 25Add BLAST1055

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei85PhosphoserineCombined sources1
Cross-linki99Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO); alternate
Cross-linki99Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin); alternate1 Publication
Modified residuei740Phosphotyrosine1 Publication1

Post-translational modificationi

Acetylated.1 Publication
Sumoylation impairs binding to and hydrolysis of ubiquitin chains. Sumoylated preferentially with SUMO2 or SUMO3. Desumoylated by SENP1. Regulated by ubiquitination on the same residue.1 Publication
Preferentially monoubiquitinated but can also be polyubiquitinated. Autodeubiquitinated. Ubiquitination activates the enzymatic activity either by preventing sumoylation or by allowing novel interactions.1 Publication
Phosphorylation in the C-terminal by SYK regulates USP25 cellular levels.2 Publications

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ9UHP3.
MaxQBiQ9UHP3.
PaxDbiQ9UHP3.
PeptideAtlasiQ9UHP3.
PRIDEiQ9UHP3.

PTM databases

iPTMnetiQ9UHP3.
PhosphoSitePlusiQ9UHP3.

Expressioni

Tissue specificityi

Isoform USP25a is found in most adult and fetal tissues; expression is moderately high in testis, pancreas, kidney, skeletal muscle, liver, lung, placenta, brain, heart, but very low in peripheral blood, colon, small intestine, ovary, prostate, thymus and spleen. Isoform USP25b is found in all tissues except heart and skeletal muscle. Isoform USP25m is heart and skeletal muscle specific.2 Publications

Inductioni

The muscle-specific isoform (USP25m) is up-regulated during myocyte differentiation. Levels increase up to 100-fold towards completion of differentiation.1 Publication

Gene expression databases

BgeeiENSG00000155313.
CleanExiHS_USP21.
HS_USP25.
ExpressionAtlasiQ9UHP3. baseline and differential.
GenevisibleiQ9UHP3. HS.

Organism-specific databases

HPAiHPA018297.
HPA024142.

Interactioni

Subunit structurei

Homodimer or oligomer. Interacts with ACTA1 (via its C-terminus); the interaction occurs for all isoforms but is strongest for isoform USP25m in muscle differentiating cells. Interacts (isoform USP25m only) with MYBPC1; the interaction prevents proteasomal degradation of MYBPC1. Interacts (isoform USP25m only) with FLNC (via filament repeats 17-18, 20-21 and 24). Interacts with GAPDH. Interacts with SUMO3; the interaction sumoylates efficiently USP25. Interacts with SUMO2; the interaction sumoylates efficiently USP25. Interacts with SUMO1; the interaction only weakly sumoylates USP25. Interacts with SYK; phosphorylates USP25 and regulates USP25 intracellular levels.4 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
MAGEB4O154813EBI-2513462,EBI-751857
RAD23AP547257EBI-2513462,EBI-746453
SUMO2P619565EBI-2513462,EBI-473220
SYKP434056EBI-2513462,EBI-78302
ZNF426Q9BUY53EBI-2513462,EBI-743265

GO - Molecular functioni

  • ATPase binding Source: ParkinsonsUK-UCL
  • SUMO binding Source: UniProtKB
  • ubiquitin binding Source: ParkinsonsUK-UCL
  • ubiquitin protein ligase binding Source: ParkinsonsUK-UCL

Protein-protein interaction databases

BioGridi118895. 45 interactors.
IntActiQ9UHP3. 24 interactors.
MINTiMINT-1188384.
STRINGi9606.ENSP00000285679.

Structurei

Secondary structure

11055
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi12 – 27Combined sources16
Helixi33 – 43Combined sources11
Helixi47 – 55Combined sources9
Beta strandi61 – 64Combined sources4
Beta strandi69 – 71Combined sources3
Helixi100 – 116Combined sources17
Helixi125 – 136Combined sources12

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2MUXNMR-A1-146[»]
ProteinModelPortaliQ9UHP3.
SMRiQ9UHP3.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini14 – 57UBA-likeAdd BLAST44
Domaini97 – 116UIM 1PROSITE-ProRule annotationAdd BLAST20
Domaini123 – 140UIM 2PROSITE-ProRule annotationAdd BLAST18
Domaini169 – 657USPAdd BLAST489

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni77 – 102SUMO interaction domain (SIM)Add BLAST26

Coiled coil

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Coiled coili541 – 578Sequence analysisAdd BLAST38
Coiled coili684 – 717Sequence analysisAdd BLAST34

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi89 – 95Required for SUMO paralog-specific binding7

Sequence similaritiesi

Belongs to the peptidase C19 family.Curated
Contains 1 UBA-like domain.Curated
Contains 2 UIM (ubiquitin-interacting motif) domains.PROSITE-ProRule annotation
Contains 1 USP domain.Curated

Keywords - Domaini

Coiled coil, Repeat

Phylogenomic databases

eggNOGiKOG1863. Eukaryota.
COG5077. LUCA.
GeneTreeiENSGT00390000016082.
HOGENOMiHOG000007956.
HOVERGENiHBG056030.
InParanoidiQ9UHP3.
KOiK11849.
OMAiNMQGIIM.
OrthoDBiEOG091G00QR.
PhylomeDBiQ9UHP3.
TreeFamiTF329035.

Family and domain databases

InterProiIPR001394. Peptidase_C19_UCH.
IPR009060. UBA-like.
IPR003903. UIM_dom.
IPR018200. USP_CS.
IPR028889. USP_dom.
[Graphical view]
PfamiPF00443. UCH. 1 hit.
PF02809. UIM. 2 hits.
[Graphical view]
SMARTiSM00726. UIM. 1 hit.
[Graphical view]
SUPFAMiSSF46934. SSF46934. 1 hit.
PROSITEiPS50330. UIM. 1 hit.
PS00972. USP_1. 1 hit.
PS00973. USP_2. 1 hit.
PS50235. USP_3. 1 hit.
[Graphical view]

Sequences (3)i

Sequence statusi: Complete.

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

Isoform USP25a (identifier: Q9UHP3-2) [UniParc]FASTAAdd to basket

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
MTVEQNVLQQ SAAQKHQQTF LNQLREITGI NDTQILQQAL KDSNGNLELA
60 70 80 90 100
VAFLTAKNAK TPQQEETTYY QTALPGNDRY ISVGSQADTN VIDLTGDDKD
110 120 130 140 150
DLQRAIALSL AESNRAFRET GITDEEQAIS RVLEASIAEN KACLKRTPTE
160 170 180 190 200
VWRDSRNPYD RKRQDKAPVG LKNVGNTCWF SAVIQSLFNL LEFRRLVLNY
210 220 230 240 250
KPPSNAQDLP RNQKEHRNLP FMRELRYLFA LLVGTKRKYV DPSRAVEILK
260 270 280 290 300
DAFKSNDSQQ QDVSEFTHKL LDWLEDAFQM KAEEETDEEK PKNPMVELFY
310 320 330 340 350
GRFLAVGVLE GKKFENTEMF GQYPLQVNGF KDLHECLEAA MIEGEIESLH
360 370 380 390 400
SENSGKSGQE HWFTELPPVL TFELSRFEFN QALGRPEKIH NKLEFPQVLY
410 420 430 440 450
LDRYMHRNRE ITRIKREEIK RLKDYLTVLQ QRLERYLSYG SGPKRFPLVD
460 470 480 490 500
VLQYALEFAS SKPVCTSPVD DIDASSPPSG SIPSQTLPST TEQQGALSSE
510 520 530 540 550
LPSTSPSSVA AISSRSVIHK PFTQSRIPPD LPMHPAPRHI TEEELSVLES
560 570 580 590 600
CLHRWRTEIE NDTRDLQESI SRIHRTIELM YSDKSMIQVP YRLHAVLVHE
610 620 630 640 650
GQANAGHYWA YIFDHRESRW MKYNDIAVTK SSWEELVRDS FGGYRNASAY
660 670 680 690 700
CLMYINDKAQ FLIQEEFNKE TGQPLVGIET LPPDLRDFVE EDNQRFEKEL
710 720 730 740 750
EEWDAQLAQK ALQEKLLASQ KLRESETSVT TAQAAGDPEY LEQPSRSDFS
760 770 780 790 800
KHLKEETIQI ITKASHEHED KSPETVLQSA IKLEYARLVK LAQEDTPPET
810 820 830 840 850
DYRLHHVVVY FIQNQAPKKI IEKTLLEQFG DRNLSFDERC HNIMKVAQAK
860 870 880 890 900
LEMIKPEEVN LEEYEEWHQD YRKFRETTMY LIIGLENFQR ESYIDSLLFL
910 920 930 940 950
ICAYQNNKEL LSKGLYRGHD EELISHYRRE CLLKLNEQAA ELFESGEDRE
960 970 980 990 1000
VNNGLIIMNE FIVPFLPLLL VDEMEEKDIL AVEDMRNRWC SYLGQEMEPH
1010 1020 1030 1040 1050
LQEKLTDFLP KLLDCSMEIK SFHEPPKLPS YSTHELCERF ARIMLSLSRT

PADGR
Length:1,055
Mass (Da):122,218
Last modified:August 10, 2010 - v4
Checksum:i0B9CECDCAD619CF2
GO
Isoform USP25b (identifier: Q9UHP3-1) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     779-779: S → SIMMTPNMQGIIMAIGKSRSVYDRCGPEAGFFK

Show »
Length:1,087
Mass (Da):125,750
Checksum:i8F852D91651B2C6E
GO
Isoform USP25m (identifier: Q9UHP3-3) [UniParc]FASTAAdd to basket
Also known as: Muscle-specific isoform

The sequence of this isoform differs from the canonical sequence as follows:
     779-779: S → SKPENTTSQPLSNQRVVEVAIPHVGKFMIESKEGGYDDEIMMTPNMQGIIMAIGKSRSVYDRCGPEAGFFK

Show »
Length:1,125
Mass (Da):129,963
Checksum:i85236A294FFEFD60
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti544E → K in AAF32263 (PubMed:10644437).Curated1
Sequence conflicti544E → K in ACN76567 (Ref. 3) Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_039632779S → SIMMTPNMQGIIMAIGKSRS VYDRCGPEAGFFK in isoform USP25b. 1 Publication1
Alternative sequenceiVSP_039631779S → SKPENTTSQPLSNQRVVEVA IPHVGKFMIESKEGGYDDEI MMTPNMQGIIMAIGKSRSVY DRCGPEAGFFK in isoform USP25m. 1 Publication1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF170562 mRNA. Translation: AAF32263.1.
AF134213 mRNA. Translation: AAF24998.1.
FJ763652 mRNA. Translation: ACN76567.1.
CH471079 Genomic DNA. Translation: EAX10041.1.
BC075792 mRNA. Translation: AAH75792.1.
AK022574 mRNA. Translation: BAB14107.1.
CCDSiCCDS33515.1. [Q9UHP3-2]
CCDS63336.1. [Q9UHP3-3]
CCDS63337.1. [Q9UHP3-1]
RefSeqiNP_001269970.1. NM_001283041.1. [Q9UHP3-3]
NP_001269971.1. NM_001283042.1. [Q9UHP3-1]
NP_037528.3. NM_013396.4. [Q9UHP3-2]
UniGeneiHs.743994.

Genome annotation databases

EnsembliENST00000285679; ENSP00000285679; ENSG00000155313. [Q9UHP3-2]
ENST00000285681; ENSP00000285681; ENSG00000155313. [Q9UHP3-1]
ENST00000400183; ENSP00000383044; ENSG00000155313. [Q9UHP3-3]
GeneIDi29761.
KEGGihsa:29761.
UCSCiuc002yjy.3. human. [Q9UHP3-2]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF170562 mRNA. Translation: AAF32263.1.
AF134213 mRNA. Translation: AAF24998.1.
FJ763652 mRNA. Translation: ACN76567.1.
CH471079 Genomic DNA. Translation: EAX10041.1.
BC075792 mRNA. Translation: AAH75792.1.
AK022574 mRNA. Translation: BAB14107.1.
CCDSiCCDS33515.1. [Q9UHP3-2]
CCDS63336.1. [Q9UHP3-3]
CCDS63337.1. [Q9UHP3-1]
RefSeqiNP_001269970.1. NM_001283041.1. [Q9UHP3-3]
NP_001269971.1. NM_001283042.1. [Q9UHP3-1]
NP_037528.3. NM_013396.4. [Q9UHP3-2]
UniGeneiHs.743994.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2MUXNMR-A1-146[»]
ProteinModelPortaliQ9UHP3.
SMRiQ9UHP3.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi118895. 45 interactors.
IntActiQ9UHP3. 24 interactors.
MINTiMINT-1188384.
STRINGi9606.ENSP00000285679.

Protein family/group databases

MEROPSiC19.041.

PTM databases

iPTMnetiQ9UHP3.
PhosphoSitePlusiQ9UHP3.

Polymorphism and mutation databases

DMDMi302393833.

Proteomic databases

EPDiQ9UHP3.
MaxQBiQ9UHP3.
PaxDbiQ9UHP3.
PeptideAtlasiQ9UHP3.
PRIDEiQ9UHP3.

Protocols and materials databases

DNASUi29761.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000285679; ENSP00000285679; ENSG00000155313. [Q9UHP3-2]
ENST00000285681; ENSP00000285681; ENSG00000155313. [Q9UHP3-1]
ENST00000400183; ENSP00000383044; ENSG00000155313. [Q9UHP3-3]
GeneIDi29761.
KEGGihsa:29761.
UCSCiuc002yjy.3. human. [Q9UHP3-2]

Organism-specific databases

CTDi29761.
DisGeNETi29761.
GeneCardsiUSP25.
HGNCiHGNC:12624. USP25.
HPAiHPA018297.
HPA024142.
MIMi604736. gene.
neXtProtiNX_Q9UHP3.
OpenTargetsiENSG00000155313.
PharmGKBiPA37249.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG1863. Eukaryota.
COG5077. LUCA.
GeneTreeiENSGT00390000016082.
HOGENOMiHOG000007956.
HOVERGENiHBG056030.
InParanoidiQ9UHP3.
KOiK11849.
OMAiNMQGIIM.
OrthoDBiEOG091G00QR.
PhylomeDBiQ9UHP3.
TreeFamiTF329035.

Enzyme and pathway databases

BioCyciZFISH:HS08041-MONOMER.
ReactomeiR-HSA-5689880. Ub-specific processing proteases.

Miscellaneous databases

ChiTaRSiUSP25. human.
GenomeRNAii29761.
PROiQ9UHP3.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000155313.
CleanExiHS_USP21.
HS_USP25.
ExpressionAtlasiQ9UHP3. baseline and differential.
GenevisibleiQ9UHP3. HS.

Family and domain databases

InterProiIPR001394. Peptidase_C19_UCH.
IPR009060. UBA-like.
IPR003903. UIM_dom.
IPR018200. USP_CS.
IPR028889. USP_dom.
[Graphical view]
PfamiPF00443. UCH. 1 hit.
PF02809. UIM. 2 hits.
[Graphical view]
SMARTiSM00726. UIM. 1 hit.
[Graphical view]
SUPFAMiSSF46934. SSF46934. 1 hit.
PROSITEiPS50330. UIM. 1 hit.
PS00972. USP_1. 1 hit.
PS00973. USP_2. 1 hit.
PS50235. USP_3. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiUBP25_HUMAN
AccessioniPrimary (citable) accession number: Q9UHP3
Secondary accession number(s): C0LSZ0, Q6DHZ9, Q9H9W1
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 30, 2000
Last sequence update: August 10, 2010
Last modified: November 30, 2016
This is version 163 of the entry and version 4 of the sequence. [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 21
    Human chromosome 21: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  4. Peptidase families
    Classification of peptidase families and list of entries
  5. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.