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Protein

Ubiquitin carboxyl-terminal hydrolase 6

Gene

USP6

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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
  • 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

  • activation of GTPase activity Source: GO_Central
  • cellular protein modification process Source: UniProtKB
  • intracellular protein transport Source: GO_Central
  • protein deubiquitination Source: UniProtKB
  • regulation of vesicle fusion Source: GO_Central
  • regulation of vesicle-mediated transport Source: UniProtKB
  • ubiquitin-dependent protein catabolic process Source: InterPro

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.

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.
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.

PTM databases

iPTMnetiP35125.
PhosphoSitePlusiP35125.

Expressioni

Tissue specificityi

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

Gene expression databases

BgeeiENSG00000129204.
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

Show more details

GO - Molecular functioni

  • calmodulin binding Source: UniProtKB
  • Rab GTPase binding Source: GO_Central

Protein-protein interaction databases

BioGridi114552. 13 interactors.
IntActiP35125. 5 interactors.
MINTiMINT-2865848.
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.
GeneTreeiENSGT00860000133698.
HOGENOMiHOG000154762.
InParanoidiP35125.
KOiK11837.
OMAiVHDSNIK.
OrthoDBiEOG091G01VD.
PhylomeDBiP35125.
TreeFamiTF324190.

Family and domain databases

InterProiView protein in InterPro
IPR001394. Peptidase_C19_UCH.
IPR000195. Rab-GTPase-TBC_dom.
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.
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

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

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

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: September 27, 2017
This is version 148 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 chromosome 17
    Human chromosome 17: 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. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. Peptidase families
    Classification of peptidase families and list of entries
  6. SIMILARITY comments
    Index of protein domains and families