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Protein

Ubiquitin carboxyl-terminal hydrolase 6

Gene

USP6

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

Functioni

Deubiquitinase with an ATP-independent isopeptidase activity, cleaving at the C-terminus of the ubiquitin moiety. Catalyzes its own deubiquitination. In vitro, isoform 2, but not isoform 3, shows deubiquitinating activity. Promotes plasma membrane localization of ARF6 and selectively regulates ARF6-dependent endocytic protein trafficking. Is able to initiate tumorigenesis by inducing the production of matrix metalloproteinases following NF-kappa-B activation.3 Publications

Miscellaneous

The USP6 gene only exists in the primate lineage.

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 sitei541Nucleophile1
Active sitei1328Proton acceptorPROSITE-ProRule annotation1

GO - Molecular functioni

  • calmodulin binding Source: UniProtKB-KW
  • cysteine-type endopeptidase activity Source: UniProtKB
  • GTPase activator activity Source: GO_Central
  • nucleic acid binding Source: ProtInc
  • Rab GTPase binding Source: GO_Central
  • thiol-dependent ubiquitin-specific protease activity Source: UniProtKB

GO - Biological processi

Keywordsi

Molecular functionCalmodulin-binding, Hydrolase, Protease, Thiol protease
Biological processUbl conjugation pathway

Enzyme and pathway databases

SIGNORiP35125

Protein family/group databases

MEROPSiC19.009

Names & Taxonomyi

Protein namesi
Recommended name:
Ubiquitin carboxyl-terminal hydrolase 6 (EC:3.4.19.12)
Alternative name(s):
Deubiquitinating enzyme 6
Proto-oncogene TRE-2
Ubiquitin thioesterase 6
Ubiquitin-specific-processing protease 6
Gene namesi
Name:USP6
Synonyms:HRP1, TRE2
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 17

Organism-specific databases

EuPathDBiHostDB:ENSG00000129204.16
HGNCiHGNC:12629 USP6
MIMi604334 gene
neXtProtiNX_P35125

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

Cell membrane, Cytoplasm, Endosome, Membrane

Pathology & Biotechi

Involvement in diseasei

A chromosomal aberration involving USP6 is a common genetic feature of aneurysmal bone cyst, a benign osseous neoplasm. Translocation t(16;17)(q22;p13) with CDH11. The translocation generates a fusion gene in which the strong CDH11 promoter is fused to the entire USP6 coding sequence, resulting in USP6 transcriptional up-regulation (PubMed:15026324).1 Publication

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi150T → R: Does not restore GAP activity in yeast complementation assay. 1 Publication1
Mutagenesisi187R → Q: Does not restore GAP activity in yeast complementation assay. 1 Publication1
Mutagenesisi541C → S: Loss of enzyme activity. 1 Publication1

Keywords - Diseasei

Proto-oncogene

Organism-specific databases

DisGeNETi9098
MalaCardsiUSP6
OpenTargetsiENSG00000129204
PharmGKBiPA37254

Polymorphism and mutation databases

BioMutaiUSP6
DMDMi50403738

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000806251 – 1406Ubiquitin carboxyl-terminal hydrolase 6Add BLAST1406

Post-translational modificationi

Monubiquitinated; ubiquitination is calmodulin and calcium dependent.1 Publication

Keywords - PTMi

Ubl conjugation

Proteomic databases

EPDiP35125
MaxQBiP35125
PaxDbiP35125
PeptideAtlasiP35125
PRIDEiP35125
ProteomicsDBi54980
54981 [P35125-2]
54982 [P35125-3]

PTM databases

iPTMnetiP35125
PhosphoSitePlusiP35125

Expressioni

Tissue specificityi

Testis specific. Expressed in various cancer cell lines.2 Publications

Gene expression databases

BgeeiENSG00000129204 Expressed in 231 organ(s), highest expression level in brain
CleanExiHS_USP6
ExpressionAtlasiP35125 baseline and differential
GenevisibleiP35125 HS

Organism-specific databases

HPAiHPA046969

Interactioni

Subunit structurei

Interacts with RAC1 and CDC42. Interacts (via Rab-GAP TBC domain) with ARF6. Interacts with calmodulin (CALM1, CALM2 and/or CALM3); the interaction is calcium-dependent.3 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi114552, 17 interactors
IntActiP35125, 5 interactors
STRINGi9606.ENSP00000250066

Structurei

3D structure databases

ProteinModelPortaliP35125
SMRiP35125
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini100 – 292Rab-GAP TBCPROSITE-ProRule annotationAdd BLAST193
Domaini532 – 1369USPAdd BLAST838

Domaini

The Rab-GAP TBC domain lacks GTPase activator activity but is necessary for interaction with ARF6.

Sequence similaritiesi

Belongs to the peptidase C19 family.Curated

Phylogenomic databases

eggNOGiKOG1102 Eukaryota
KOG1870 Eukaryota
COG5210 LUCA
COG5560 LUCA
GeneTreeiENSGT00670000097750
HOGENOMiHOG000154762
InParanoidiP35125
KOiK11837
OMAiVHDSNIK
OrthoDBiEOG091G01VD
PhylomeDBiP35125
TreeFamiTF324190

Family and domain databases

InterProiView protein in InterPro
IPR038765 Papain_like_cys_pep_sf
IPR001394 Peptidase_C19_UCH
IPR000195 Rab-GTPase-TBC_dom
IPR035969 Rab-GTPase_TBC_sf
IPR018200 USP_CS
IPR028889 USP_dom
PfamiView protein in Pfam
PF00566 RabGAP-TBC, 1 hit
PF00443 UCH, 1 hit
SMARTiView protein in SMART
SM00164 TBC, 1 hit
SUPFAMiSSF47923 SSF47923, 2 hits
SSF54001 SSF54001, 3 hits
PROSITEiView protein in PROSITE
PS50086 TBC_RABGAP, 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 1 potential isoform that is computationally mapped.Show allAlign All

Isoform 1 (identifier: P35125-1) [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
MDMVENADSL QAQERKDILM KYDKGHRAGL PEDKGPEPVG INSSIDRFGI
60 70 80 90 100
LHETELPPVT AREAKKIRRE MTRTSKWMEM LGEWETYKHS SKLIDRVYKG
110 120 130 140 150
IPMNIRGPVW SVLLNIQEIK LKNPGRYQIM KERGKRSSEH IHHIDLDVRT
160 170 180 190 200
TLRNHVFFRD RYGAKQRELF YILLAYSEYN PEVGYCRDLS HITALFLLYL
210 220 230 240 250
PEEDAFWALV QLLASERHSL PGFHSPNGGT VQGLQDQQEH VVPKSQPKTM
260 270 280 290 300
WHQDKEGLCG QCASLGCLLR NLIDGISLGL TLRLWDVYLV EGEQVLMPIT
310 320 330 340 350
SIALKVQQKR LMKTSRCGLW ARLRNQFFDT WAMNDDTVLK HLRASTKKLT
360 370 380 390 400
RKQGDLPPPA KREQGSLAPR PVPASRGGKT LCKGYRQAPP GPPAQFQRPI
410 420 430 440 450
CSASPPWASR FSTPCPGGAV REDTYPVGTQ GVPSLALAQG GPQGSWRFLE
460 470 480 490 500
WKSMPRLPTD LDIGGPWFPH YDFEWSCWVR AISQEDQLAT CWQAEHCGEV
510 520 530 540 550
HNKDMSWPEE MSFTANSSKI DRQKVPTEKG ATGLSNLGNT CFMNSSIQCV
560 570 580 590 600
SNTQPLTQYF ISGRHLYELN RTNPIGMKGH MAKCYGDLVQ ELWSGTQKSV
610 620 630 640 650
APLKLRRTIA KYAPKFDGFQ QQDSQELLAF LLDGLHEDLN RVHEKPYVEL
660 670 680 690 700
KDSDGRPDWE VAAEAWDNHL RRNRSIIVDL FHGQLRSQVK CKTCGHISVR
710 720 730 740 750
FDPFNFLSLP LPMDSYMDLE ITVIKLDGTT PVRYGLRLNM DEKYTGLKKQ
760 770 780 790 800
LRDLCGLNSE QILLAEVHDS NIKNFPQDNQ KVQLSVSGFL CAFEIPVPSS
810 820 830 840 850
PISASSPTQI DFSSSPSTNG MFTLTTNGDL PKPIFIPNGM PNTVVPCGTE
860 870 880 890 900
KNFTNGMVNG HMPSLPDSPF TGYIIAVHRK MMRTELYFLS PQENRPSLFG
910 920 930 940 950
MPLIVPCTVH TRKKDLYDAV WIQVSWLARP LPPQEASIHA QDRDNCMGYQ
960 970 980 990 1000
YPFTLRVVQK DGNSCAWCPQ YRFCRGCKID CGEDRAFIGN AYIAVDWHPT
1010 1020 1030 1040 1050
ALHLRYQTSQ ERVVDKHESV EQSRRAQAEP INLDSCLRAF TSEEELGESE
1060 1070 1080 1090 1100
MYYCSKCKTH CLATKKLDLW RLPPFLIIHL KRFQFVNDQW IKSQKIVRFL
1110 1120 1130 1140 1150
RESFDPSAFL VPRDPALCQH KPLTPQGDEL SKPRILAREV KKVDAQSSAG
1160 1170 1180 1190 1200
KEDMLLSKSP SSLSANISSS PKGSPSSSRK SGTSCPSSKN SSPNSSPRTL
1210 1220 1230 1240 1250
GRSKGRLRLP QIGSKNKPSS SKKNLDASKE NGAGQICELA DALSRGHMRG
1260 1270 1280 1290 1300
GSQPELVTPQ DHEVALANGF LYEHEACGNG CGDGYSNGQL GNHSEEDSTD
1310 1320 1330 1340 1350
DQREDTHIKP IYNLYAISCH SGILSGGHYI TYAKNPNCKW YCYNDSSCEE
1360 1370 1380 1390 1400
LHPDEIDTDS AYILFYEQQG IDYAQFLPKI DGKKMADTSS TDEDSESDYE

KYSMLQ
Length:1,406
Mass (Da):158,658
Last modified:July 19, 2004 - v2
Checksum:iD3A6822CEB441DB3
GO
Isoform 2 (identifier: P35125-2) [UniParc]FASTAAdd to basket
Also known as: 213(ORF2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-317: Missing.
     318-359: GLWARLRNQF...TRKQGDLPPP → MPQRLPHARQ...HRDPKDSRDA

Show »
Length:1,089
Mass (Da):121,943
Checksum:iA660606208ABD9EB
GO
Isoform 3 (identifier: P35125-3) [UniParc]FASTAAdd to basket
Also known as: 210(ORF1), oncTre210p

The sequence of this isoform differs from the canonical sequence as follows:
     774-786: NFPQDNQKVQLSV → ISPLHHLQMECSP
     787-1406: Missing.

Note: Was shown to be tumorigenic in transfected mice and seems not to act as GTPase activating protein.
Show »
Length:786
Mass (Da):89,577
Checksum:i6D5D93D2CE65D879
GO

Computationally mapped potential isoform sequencesi

There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
Q15635Q15635_HUMAN
Oncogene
USP6 tre
376Annotation score:

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti963N → I in CAA45111 (PubMed:1565468).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_051522475W → R1 PublicationCorresponds to variant dbSNP:rs8073787Ensembl.1
Natural variantiVAR_059749525V → I. Corresponds to variant dbSNP:rs2304449Ensembl.1
Natural variantiVAR_051523912R → Q1 PublicationCorresponds to variant dbSNP:rs9899177Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0108781 – 317Missing in isoform 2. 1 PublicationAdd BLAST317
Alternative sequenceiVSP_010879318 – 359GLWAR…DLPPP → MPQRLPHARQHTPLPLGSAD YRRVVSVRPQGPHRDPKDSR DA in isoform 2. 1 PublicationAdd BLAST42
Alternative sequenceiVSP_010880774 – 786NFPQD…VQLSV → ISPLHHLQMECSP in isoform 3. 1 PublicationAdd BLAST13
Alternative sequenceiVSP_010881787 – 1406Missing in isoform 3. 1 PublicationAdd BLAST620

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X63546 mRNA Translation: CAA45108.1
X63547 mRNA Translation: CAA45111.1
AY143550 mRNA Translation: AAN38838.1
AY163314 Genomic DNA Translation: AAO21348.1
CCDSiCCDS11069.2 [P35125-1]
PIRiS57867
S57868 S22158
S57874 S22155
RefSeqiNP_001291213.1, NM_001304284.1
NP_004496.2, NM_004505.3 [P35125-1]
XP_011522352.1, XM_011524050.1 [P35125-1]
XP_011522353.1, XM_011524051.2 [P35125-1]
XP_011522354.1, XM_011524052.2 [P35125-1]
XP_011522355.1, XM_011524053.2 [P35125-1]
XP_011522356.1, XM_011524054.2 [P35125-1]
XP_011522357.1, XM_011524055.2 [P35125-1]
XP_011522358.1, XM_011524056.2 [P35125-1]
XP_011522361.1, XM_011524059.2 [P35125-3]
XP_016880779.1, XM_017025290.1 [P35125-1]
UniGeneiHs.448851

Genome annotation databases

EnsembliENST00000250066; ENSP00000250066; ENSG00000129204 [P35125-1]
ENST00000572949; ENSP00000461581; ENSG00000129204 [P35125-3]
ENST00000574788; ENSP00000460380; ENSG00000129204 [P35125-1]
GeneIDi9098
KEGGihsa:9098
UCSCiuc002gau.2 human [P35125-1]

Keywords - Coding sequence diversityi

Alternative splicing, Chromosomal rearrangement, Polymorphism

Similar proteinsi

Cross-referencesi

Web resourcesi

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X63546 mRNA Translation: CAA45108.1
X63547 mRNA Translation: CAA45111.1
AY143550 mRNA Translation: AAN38838.1
AY163314 Genomic DNA Translation: AAO21348.1
CCDSiCCDS11069.2 [P35125-1]
PIRiS57867
S57868 S22158
S57874 S22155
RefSeqiNP_001291213.1, NM_001304284.1
NP_004496.2, NM_004505.3 [P35125-1]
XP_011522352.1, XM_011524050.1 [P35125-1]
XP_011522353.1, XM_011524051.2 [P35125-1]
XP_011522354.1, XM_011524052.2 [P35125-1]
XP_011522355.1, XM_011524053.2 [P35125-1]
XP_011522356.1, XM_011524054.2 [P35125-1]
XP_011522357.1, XM_011524055.2 [P35125-1]
XP_011522358.1, XM_011524056.2 [P35125-1]
XP_011522361.1, XM_011524059.2 [P35125-3]
XP_016880779.1, XM_017025290.1 [P35125-1]
UniGeneiHs.448851

3D structure databases

ProteinModelPortaliP35125
SMRiP35125
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi114552, 17 interactors
IntActiP35125, 5 interactors
STRINGi9606.ENSP00000250066

Protein family/group databases

MEROPSiC19.009

PTM databases

iPTMnetiP35125
PhosphoSitePlusiP35125

Polymorphism and mutation databases

BioMutaiUSP6
DMDMi50403738

Proteomic databases

EPDiP35125
MaxQBiP35125
PaxDbiP35125
PeptideAtlasiP35125
PRIDEiP35125
ProteomicsDBi54980
54981 [P35125-2]
54982 [P35125-3]

Protocols and materials databases

DNASUi9098
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000250066; ENSP00000250066; ENSG00000129204 [P35125-1]
ENST00000572949; ENSP00000461581; ENSG00000129204 [P35125-3]
ENST00000574788; ENSP00000460380; ENSG00000129204 [P35125-1]
GeneIDi9098
KEGGihsa:9098
UCSCiuc002gau.2 human [P35125-1]

Organism-specific databases

CTDi9098
DisGeNETi9098
EuPathDBiHostDB:ENSG00000129204.16
GeneCardsiUSP6
H-InvDBiHIX0202554
HGNCiHGNC:12629 USP6
HPAiHPA046969
MalaCardsiUSP6
MIMi604334 gene
neXtProtiNX_P35125
OpenTargetsiENSG00000129204
PharmGKBiPA37254
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG1102 Eukaryota
KOG1870 Eukaryota
COG5210 LUCA
COG5560 LUCA
GeneTreeiENSGT00670000097750
HOGENOMiHOG000154762
InParanoidiP35125
KOiK11837
OMAiVHDSNIK
OrthoDBiEOG091G01VD
PhylomeDBiP35125
TreeFamiTF324190

Enzyme and pathway databases

SIGNORiP35125

Miscellaneous databases

ChiTaRSiUSP6 human
GeneWikiiUSP6
GenomeRNAii9098
PROiPR:P35125
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000129204 Expressed in 231 organ(s), highest expression level in brain
CleanExiHS_USP6
ExpressionAtlasiP35125 baseline and differential
GenevisibleiP35125 HS

Family and domain databases

InterProiView protein in InterPro
IPR038765 Papain_like_cys_pep_sf
IPR001394 Peptidase_C19_UCH
IPR000195 Rab-GTPase-TBC_dom
IPR035969 Rab-GTPase_TBC_sf
IPR018200 USP_CS
IPR028889 USP_dom
PfamiView protein in Pfam
PF00566 RabGAP-TBC, 1 hit
PF00443 UCH, 1 hit
SMARTiView protein in SMART
SM00164 TBC, 1 hit
SUPFAMiSSF47923 SSF47923, 2 hits
SSF54001 SSF54001, 3 hits
PROSITEiView protein in PROSITE
PS50086 TBC_RABGAP, 1 hit
PS00972 USP_1, 1 hit
PS00973 USP_2, 1 hit
PS50235 USP_3, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiUBP6_HUMAN
AccessioniPrimary (citable) accession number: P35125
Secondary accession number(s): Q15634, Q86WP6, Q8IWT4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1994
Last sequence update: July 19, 2004
Last modified: October 10, 2018
This is version 156 of the entry and version 2 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

Complete proteome, Reference proteome

Documents

  1. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  2. Peptidase families
    Classification of peptidase families and list of entries
  3. SIMILARITY comments
    Index of protein domains and families
  4. Human chromosome 17
    Human chromosome 17: entries, gene names and cross-references to MIM
  5. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  6. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
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