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Protein

Ubiquitin carboxyl-terminal hydrolase 15

Gene

USP15

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

Functioni

Hydrolase that removes conjugated ubiquitin from target proteins and regulates various pathways such as the TGF-beta receptor signaling, NF-kappa-B and RNF41/NRDP1-PRKN pathways (PubMed:21947082, PubMed:22344298, PubMed:24852371, PubMed:16005295, PubMed:17318178, PubMed:19826004, PubMed:19576224). Acts as a key regulator of TGF-beta receptor signaling pathway, but the precise mechanism is still unclear: according to a report, acts by promoting deubiquitination of monoubiquitinated R-SMADs (SMAD1, SMAD2 and/or SMAD3), thereby alleviating inhibition of R-SMADs and promoting activation of TGF-beta target genes (PubMed:21947082). According to another reports, regulates the TGF-beta receptor signaling pathway by mediating deubiquitination and stabilization of TGFBR1, leading to an enhanced TGF-beta signal (PubMed:22344298). Able to mediate deubiquitination of monoubiquitinated substrates as well as 'Lys-48'-linked polyubiquitin chains, protecting them against proteasomal degradation. May also regulate gene expression and/or DNA repair through the deubiquitination of histone H2B (PubMed:24526689). Acts as an inhibitor of mitophagy by counteracting the action of parkin (PRKN): hydrolyzes cleavage of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains attached by parkin on target proteins such as MFN2, thereby reducing parkin's ability to drive mitophagy (PubMed:24852371). Acts as an associated component of COP9 signalosome complex (CSN) and regulates different pathways via this association: regulates NF-kappa-B by mediating deubiquitination of NFKBIA and deubiquitinates substrates bound to VCP (PubMed:16005295, PubMed:17318178, PubMed:19826004, PubMed:19576224). Involved in endosome organization by mediating deubiquitination of SQSTM1: ubiquitinated SQSTM1 forms a molecular bridge that restrains cognate vesicles in the perinuclear region and its deubiquitination releases target vesicles for fast transport into the cell periphery (PubMed:27368102).9 Publications
(Microbial infection) Protects APC and human papillomavirus type 16 protein E6 against degradation via the ubiquitin proteasome pathway.1 Publication

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).5 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei298NucleophilePROSITE-ProRule annotation5 Publications1
Active sitei891Proton acceptorPROSITE-ProRule annotation1

GO - Molecular functioni

  • cysteine-type endopeptidase activity Source: UniProtKB
  • identical protein binding Source: IntAct
  • SMAD binding Source: UniProtKB
  • thiol-dependent ubiquitin-specific protease activity Source: UniProtKB
  • thiol-dependent ubiquitinyl hydrolase activity Source: UniProtKB
  • transforming growth factor beta receptor binding Source: UniProtKB
  • ubiquitin modification-dependent histone binding Source: UniProtKB

GO - Biological processi

  • BMP signaling pathway Source: UniProtKB
  • histone H2B conserved C-terminal lysine deubiquitination Source: UniProtKB
  • monoubiquitinated protein deubiquitination Source: UniProtKB
  • pathway-restricted SMAD protein phosphorylation Source: UniProtKB
  • protein deubiquitination Source: UniProtKB
  • transforming growth factor beta receptor signaling pathway Source: UniProtKB
  • ubiquitin-dependent protein catabolic process Source: InterPro

Keywordsi

Molecular functionHydrolase, Protease, Thiol protease
Biological processUbl conjugation pathway

Enzyme and pathway databases

ReactomeiR-HSA-2173788 Downregulation of TGF-beta receptor signaling
R-HSA-5689603 UCH proteinases
R-HSA-5689880 Ub-specific processing proteases

Protein family/group databases

MEROPSiC19.022

Names & Taxonomyi

Protein namesi
Recommended name:
Ubiquitin carboxyl-terminal hydrolase 15 (EC:3.4.19.126 Publications)
Alternative name(s):
Deubiquitinating enzyme 15
Ubiquitin thioesterase 15
Ubiquitin-specific-processing protease 15
Unph-2
Unph4
Gene namesi
Name:USP15
Synonyms:KIAA0529
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 12

Organism-specific databases

EuPathDBiHostDB:ENSG00000135655.13
HGNCiHGNC:12613 USP15
MIMi604731 gene
neXtProtiNX_Q9Y4E8

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, Mitochondrion, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi298C → A: Loss of enzyme activity. 5 Publications1
Mutagenesisi812C → A: Loss of activity towards polyubiquitin. 2 Publications1

Organism-specific databases

DisGeNETi9958
OpenTargetsiENSG00000135655
PharmGKBiPA37239

Polymorphism and mutation databases

BioMutaiUSP15
DMDMi28381406

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedCombined sources1 Publication
ChainiPRO_00000806412 – 981Ubiquitin carboxyl-terminal hydrolase 15Add BLAST980

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylalanineCombined sources1 Publication1
Modified residuei226PhosphothreonineCombined sources1
Modified residuei229PhosphoserineCombined sources1
Modified residuei242PhosphoserineCombined sources1
Modified residuei602PhosphothreonineBy similarity1
Modified residuei961PhosphoserineCombined sources1
Modified residuei965PhosphoserineCombined sources1

Post-translational modificationi

Phosphorylated. Phosphorylation protects against ubiquitination and subsequent degradation by the proteasome.1 Publication
Ubiquitinated, leading to degradation by the proteasome.1 Publication

Keywords - PTMi

Acetylation, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ9Y4E8
PaxDbiQ9Y4E8
PeptideAtlasiQ9Y4E8
PRIDEiQ9Y4E8

PTM databases

iPTMnetiQ9Y4E8
PhosphoSitePlusiQ9Y4E8

Expressioni

Tissue specificityi

Expressed in skeletal muscle, kidney, heart, placenta, liver, thymus, lung, and ovary, with little or no expression in other tissues.

Gene expression databases

BgeeiENSG00000135655
CleanExiHS_USP15
ExpressionAtlasiQ9Y4E8 baseline and differential
GenevisibleiQ9Y4E8 HS

Organism-specific databases

HPAiHPA006237
HPA006428
HPA071014

Interactioni

Subunit structurei

A homodimer structure has been reported; however it is unclear whether the protein form a homodimer in vivo (PubMed:22001210). Identified in a complex with the COP9 signalosome complex (CSN) (PubMed:16005295). Interacts with SMAD1, SMAD2 and SMAD3; the interaction is direct (PubMed:21947082). Forms a complex with SMURF2 and SMAD7 (PubMed:22344298). Interacts with TGFBR1 (PubMed:22344298). Interacts with SART3; the interaction is direct (PubMed:24526689). May interact with RNF20 and RNF40 (PubMed:24526689). May interact with PRKN (PubMed:24852371).6 Publications
(Microbial infection) Interacts with human papillomavirus type 16 protein E6.1 Publication

Binary interactionsi

Show more details

GO - Molecular functioni

  • identical protein binding Source: IntAct
  • SMAD binding Source: UniProtKB
  • transforming growth factor beta receptor binding Source: UniProtKB
  • ubiquitin modification-dependent histone binding Source: UniProtKB

Protein-protein interaction databases

BioGridi115283, 204 interactors
DIPiDIP-50239N
IntActiQ9Y4E8, 63 interactors
MINTiQ9Y4E8
STRINGi9606.ENSP00000258123

Structurei

Secondary structure

1981
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi4 – 6Combined sources3
Helixi9 – 19Combined sources11
Beta strandi29 – 34Combined sources6
Helixi35 – 45Combined sources11
Turni46 – 48Combined sources3
Turni53 – 56Combined sources4
Helixi58 – 60Combined sources3
Helixi68 – 70Combined sources3
Beta strandi73 – 76Combined sources4
Turni86 – 88Combined sources3
Beta strandi89 – 93Combined sources5
Helixi94 – 104Combined sources11
Beta strandi114 – 120Combined sources7
Beta strandi122 – 124Combined sources3
Beta strandi127 – 129Combined sources3
Beta strandi134 – 140Combined sources7
Beta strandi143 – 152Combined sources10
Helixi158 – 168Combined sources11
Beta strandi173 – 175Combined sources3
Beta strandi177 – 184Combined sources8
Beta strandi187 – 190Combined sources4
Helixi198 – 201Combined sources4
Beta strandi208 – 213Combined sources6

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1W6VNMR-A1-120[»]
3LMNX-ray2.15A/B1-133[»]
3PPAX-ray2.35A6-223[»]
3PV1X-ray2.60A/B1-223[»]
3T9LX-ray1.50A1-222[»]
4A3OX-ray2.20A/B4-223[»]
4A3PX-ray1.40A6-223[»]
5JJWX-ray3.01B1-223[»]
ProteinModelPortaliQ9Y4E8
SMRiQ9Y4E8
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ9Y4E8

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini7 – 118DUSPPROSITE-ProRule annotationAdd BLAST112
Domaini289 – 933USPPROSITE-ProRule annotationAdd BLAST645

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni2 – 223Mediates interaction with SART31 PublicationAdd BLAST222

Sequence similaritiesi

Belongs to the peptidase C19 family.Curated

Phylogenomic databases

eggNOGiKOG1870 Eukaryota
COG5560 LUCA
GeneTreeiENSGT00670000097750
HOGENOMiHOG000264375
HOVERGENiHBG000864
InParanoidiQ9Y4E8
KOiK21343
OMAiCTEETCK
OrthoDBiEOG091G0157
PhylomeDBiQ9Y4E8
TreeFamiTF106276

Family and domain databases

InterProiView protein in InterPro
IPR035927 DUSP-like_sf
IPR006615 Pept_C19_DUSP
IPR001394 Peptidase_C19_UCH
IPR013792 RNA3'P_cycl/enolpyr_Trfase_a/b
IPR028135 Ub_USP-typ
IPR029071 Ubiquitin-like_domsf
IPR028134 USP4
IPR029346 USP_C
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
PF14533 USP7_C2, 1 hit
SMARTiView protein in SMART
SM00695 DUSP, 1 hit
SUPFAMiSSF143791 SSF143791, 1 hit
SSF54236 SSF54236, 1 hit
SSF55205 SSF55205, 1 hit
PROSITEiView protein in PROSITE
PS51283 DUSP, 1 hit
PS00972 USP_1, 1 hit
PS00973 USP_2, 1 hit
PS50235 USP_3, 1 hit

Sequences (4)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 4 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q9Y4E8-1) [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
MAEGGAADLD TQRSDIATLL KTSLRKGDTW YLVDSRWFKQ WKKYVGFDSW
60 70 80 90 100
DKYQMGDQNV YPGPIDNSGL LKDGDAQSLK EHLIDELDYI LLPTEGWNKL
110 120 130 140 150
VSWYTLMEGQ EPIARKVVEQ GMFVKHCKVE VYLTELKLCE NGNMNNVVTR
160 170 180 190 200
RFSKADTIDT IEKEIRKIFS IPDEKETRLW NKYMSNTFEP LNKPDSTIQD
210 220 230 240 250
AGLYQGQVLV IEQKNEDGTW PRGPSTPKSP GASNFSTLPK ISPSSLSNNY
260 270 280 290 300
NNMNNRNVKN SNYCLPSYTA YKNYDYSEPG RNNEQPGLCG LSNLGNTCFM
310 320 330 340 350
NSAIQCLSNT PPLTEYFLND KYQEELNFDN PLGMRGEIAK SYAELIKQMW
360 370 380 390 400
SGKFSYVTPR AFKTQVGRFA PQFSGYQQQD CQELLAFLLD GLHEDLNRIR
410 420 430 440 450
KKPYIQLKDA DGRPDKVVAE EAWENHLKRN DSIIVDIFHG LFKSTLVCPE
460 470 480 490 500
CAKISVTFDP FCYLTLPLPM KKERTLEVYL VRMDPLTKPM QYKVVVPKIG
510 520 530 540 550
NILDLCTALS ALSGIPADKM IVTDIYNHRF HRIFAMDENL SSIMERDDIY
560 570 580 590 600
VFEININRTE DTEHVIIPVC LREKFRHSSY THHTGSSLFG QPFLMAVPRN
610 620 630 640 650
NTEDKLYNLL LLRMCRYVKI STETEETEGS LHCCKDQNIN GNGPNGIHEE
660 670 680 690 700
GSPSEMETDE PDDESSQDQE LPSENENSQS EDSVGGDNDS ENGLCTEDTC
710 720 730 740 750
KGQLTGHKKR LFTFQFNNLG NTDINYIKDD TRHIRFDDRQ LRLDERSFLA
760 770 780 790 800
LDWDPDLKKR YFDENAAEDF EKHESVEYKP PKKPFVKLKD CIELFTTKEK
810 820 830 840 850
LGAEDPWYCP NCKEHQQATK KLDLWSLPPV LVVHLKRFSY SRYMRDKLDT
860 870 880 890 900
LVDFPINDLD MSEFLINPNA GPCRYNLIAV SNHYGGMGGG HYTAFAKNKD
910 920 930 940 950
DGKWYYFDDS SVSTASEDQI VSKAAYVLFY QRQDTFSGTG FFPLDRETKG
960 970 980
ASAATGIPLE SDEDSNDNDN DIENENCMHT N
Length:981
Mass (Da):112,419
Last modified:February 12, 2003 - v3
Checksum:iE81FEB9DE57F7089
GO
Isoform 2 (identifier: Q9Y4E8-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     228-256: Missing.

Show »
Length:952
Mass (Da):109,297
Checksum:i852ED3768FB5725A
GO
Isoform 3 (identifier: Q9Y4E8-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     217-256: DGTWPRGPSTPKSPGASNFSTLPKISPSSLSNNYNNMNNR → QKNEDGTWPRGPSTP

Show »
Length:956
Mass (Da):109,796
Checksum:iF9F83D3886404B11
GO
Isoform 4 (identifier: Q9Y4E8-4) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     229-235: SPGASNF → KPLEQSC
     236-981: Missing.

Show »
Length:235
Mass (Da):27,094
Checksum:iF69B0D2783E2A443
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti559T → A in AAG28973 (Ref. 9) Curated1
Sequence conflicti747S → F in AAI25124 (PubMed:15489334).Curated1
Sequence conflicti968N → H in AAG28973 (Ref. 9) Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_005260217 – 256DGTWP…NMNNR → QKNEDGTWPRGPSTP in isoform 3. 1 PublicationAdd BLAST40
Alternative sequenceiVSP_005261228 – 256Missing in isoform 2. 3 PublicationsAdd BLAST29
Alternative sequenceiVSP_045165229 – 235SPGASNF → KPLEQSC in isoform 4. 2 Publications7
Alternative sequenceiVSP_045166236 – 981Missing in isoform 4. 2 PublicationsAdd BLAST746

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF106069 mRNA Translation: AAD52099.1
AB011101 mRNA Translation: BAA25455.2
AF153604 mRNA Translation: AAD41086.1
AK023703 mRNA Translation: BAB14648.1
AK292337 mRNA Translation: BAF85026.1
AC048342 Genomic DNA No translation available.
AC079035 Genomic DNA No translation available.
AC117370 Genomic DNA No translation available.
BC020688 mRNA Translation: AAH20688.1
BC063454 mRNA Translation: AAH63454.1
BC125123 mRNA Translation: AAI25124.1
AF013990 mRNA Translation: AAG28973.1
CCDSiCCDS58250.1 [Q9Y4E8-4]
CCDS58251.1 [Q9Y4E8-1]
CCDS8963.1 [Q9Y4E8-2]
RefSeqiNP_001239007.1, NM_001252078.1 [Q9Y4E8-1]
NP_001239008.1, NM_001252079.1 [Q9Y4E8-4]
NP_006304.1, NM_006313.2 [Q9Y4E8-2]
UniGeneiHs.434951

Genome annotation databases

EnsembliENST00000280377; ENSP00000280377; ENSG00000135655 [Q9Y4E8-1]
ENST00000312635; ENSP00000309240; ENSG00000135655 [Q9Y4E8-4]
ENST00000353364; ENSP00000258123; ENSG00000135655 [Q9Y4E8-2]
GeneIDi9958
KEGGihsa:9958
UCSCiuc001sra.4 human [Q9Y4E8-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiUBP15_HUMAN
AccessioniPrimary (citable) accession number: Q9Y4E8
Secondary accession number(s): Q08AL5
, Q9H8G9, Q9HCA6, Q9UNP0, Q9Y5B5
Entry historyiIntegrated into UniProtKB/Swiss-Prot: December 1, 2000
Last sequence update: February 12, 2003
Last modified: May 23, 2018
This is version 181 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, Direct protein sequencing, Reference proteome

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