Reviewed, UniProtKB/Swiss-Prot P35125 (UBP6_HUMAN)

Names and origin

Protein names

Recommended name:
    Ubiquitin carboxyl-terminal hydrolase 6
    EC=3.1.2.15
Alternative name(s):
    Ubiquitin thioesterase 6
    Ubiquitin-specific-processing protease 6
    Deubiquitinating enzyme 6
    Proto-oncogene TRE-2

Gene names

Name:	USP6
Synonyms:	HRP1, TRE2

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	1406 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Has an ATP-independent isopeptidase activity, cleaving at the C-terminus of the ubiquitin moiety. In vitro, isoform 2, but not isoform 3, shows deubiquitinating activity.
Catalytic activity	Ubiquitin C-terminal thioester + H2O = ubiquitin + a thiol.
Tissue specificity	Testis specific. Expressed in various cancer cell lines. Ref.1 Ref.2
Involvement in disease	Involved in tumorigenesis.
Miscellaneous	The USP6 gene only exists in the primate lineage.
Sequence similarities	Belongs to the peptidase C19 family. Contains 1 Rab-GAP TBC domain.

Ontologies

Keywords
Biological process	Ubl conjugation pathway
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Proto-oncogene
Molecular function	Hydrolase Protease Thiol protease
Technical term	Complete proteome
Gene Ontology (GO)
Biological process	protein modification process Non-traceable author statement. Source: UniProtKB regulation of Rab GTPase activity Inferred from electronic annotation. Source: InterPro ubiquitin-dependent protein catabolic process Inferred from electronic annotation. Source: InterPro
Cellular component	lysosome Traceable author statement. Source: ProtInc
Molecular function	Rab GTPase activator activity Inferred from electronic annotation. Source: InterPro cysteine-type endopeptidase activity Traceable author statement. Source: UniProtKB nucleic acid binding Ref.1 Traceable author statement. Source: ProtInc protein binding Inferred from physical interaction. Source: IntAct ubiquitin thiolesterase activity Inferred from electronic annotation. Source: EC
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
ANKRD44	Q8N8A2	2	EBI-954590,EBI-1245329
MYL2	P10916	2	EBI-954590,EBI-725770

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P35125-1)

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.

Isoform 2 (identifier: P35125-2)

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

Isoform 3 (identifier: P35125-3)

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.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 1406	1406	Ubiquitin carboxyl-terminal hydrolase 6		PRO_0000080625
Regions
	Domain	100 – 292	193	Rab-GAP TBC
Sites
	Active site	541	1	By similarity
	Active site	1320	1	By similarity
	Active site	1328	1	By similarity
Natural variations
	Alternative sequence	1 – 317	317	Missing in isoform 2.		VSP_010878
	Alternative sequence	318 – 359	42	GLWAR…DLPPP → MPQRLPHARQHTPLPLGSAD YRRVVSVRPQGPHRDPKDSR DA in isoform 2.		VSP_010879
	Alternative sequence	774 – 786	13	NFPQD…VQLSV → ISPLHHLQMECSP in isoform 3.		VSP_010880
	Alternative sequence	787 – 1406	620	Missing in isoform 3.		VSP_010881
	Natural variant	475	1	W → R: dbSNP rs8073787. Ref.1		VAR_051522
	Natural variant	525	1	V → I: dbSNP rs2304449.		VAR_059749
	Natural variant	912	1	R → Q: dbSNP rs9899177. Ref.1		VAR_051523
	Natural variant	1330	1	I → V: dbSNP rs1053611.		VAR_051524
Experimental info
	Mutagenesis	150	1	T → R: Does not restore GAP activity in yeast complementation assay. Ref.4
	Mutagenesis	187	1	R → Q: Does not restore GAP activity in yeast complementation assay. Ref.4
	Sequence conflict	963	1	N → I in CAA45111. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified July 19, 2004. Version 2. Checksum: D3A6822CEB441DB3	FASTA	1,406	158,658
	10 20 30 40 50 60 MDMVENADSL QAQERKDILM KYDKGHRAGL PEDKGPEPVG INSSIDRFGI LHETELPPVT 70 80 90 100 110 120 AREAKKIRRE MTRTSKWMEM LGEWETYKHS SKLIDRVYKG IPMNIRGPVW SVLLNIQEIK 130 140 150 160 170 180 LKNPGRYQIM KERGKRSSEH IHHIDLDVRT TLRNHVFFRD RYGAKQRELF YILLAYSEYN 190 200 210 220 230 240 PEVGYCRDLS HITALFLLYL PEEDAFWALV QLLASERHSL PGFHSPNGGT VQGLQDQQEH 250 260 270 280 290 300 VVPKSQPKTM WHQDKEGLCG QCASLGCLLR NLIDGISLGL TLRLWDVYLV EGEQVLMPIT 310 320 330 340 350 360 SIALKVQQKR LMKTSRCGLW ARLRNQFFDT WAMNDDTVLK HLRASTKKLT RKQGDLPPPA 370 380 390 400 410 420 KREQGSLAPR PVPASRGGKT LCKGYRQAPP GPPAQFQRPI CSASPPWASR FSTPCPGGAV 430 440 450 460 470 480 REDTYPVGTQ GVPSLALAQG GPQGSWRFLE WKSMPRLPTD LDIGGPWFPH YDFEWSCWVR 490 500 510 520 530 540 AISQEDQLAT CWQAEHCGEV HNKDMSWPEE MSFTANSSKI DRQKVPTEKG ATGLSNLGNT 550 560 570 580 590 600 CFMNSSIQCV SNTQPLTQYF ISGRHLYELN RTNPIGMKGH MAKCYGDLVQ ELWSGTQKSV 610 620 630 640 650 660 APLKLRRTIA KYAPKFDGFQ QQDSQELLAF LLDGLHEDLN RVHEKPYVEL KDSDGRPDWE 670 680 690 700 710 720 VAAEAWDNHL RRNRSIIVDL FHGQLRSQVK CKTCGHISVR FDPFNFLSLP LPMDSYMDLE 730 740 750 760 770 780 ITVIKLDGTT PVRYGLRLNM DEKYTGLKKQ LRDLCGLNSE QILLAEVHDS NIKNFPQDNQ 790 800 810 820 830 840 KVQLSVSGFL CAFEIPVPSS PISASSPTQI DFSSSPSTNG MFTLTTNGDL PKPIFIPNGM 850 860 870 880 890 900 PNTVVPCGTE KNFTNGMVNG HMPSLPDSPF TGYIIAVHRK MMRTELYFLS PQENRPSLFG 910 920 930 940 950 960 MPLIVPCTVH TRKKDLYDAV WIQVSWLARP LPPQEASIHA QDRDNCMGYQ YPFTLRVVQK 970 980 990 1000 1010 1020 DGNSCAWCPQ YRFCRGCKID CGEDRAFIGN AYIAVDWHPT ALHLRYQTSQ ERVVDKHESV 1030 1040 1050 1060 1070 1080 EQSRRAQAEP INLDSCLRAF TSEEELGESE MYYCSKCKTH CLATKKLDLW RLPPFLIIHL 1090 1100 1110 1120 1130 1140 KRFQFVNDQW IKSQKIVRFL RESFDPSAFL VPRDPALCQH KPLTPQGDEL SKPRILAREV 1150 1160 1170 1180 1190 1200 KKVDAQSSAG KEDMLLSKSP SSLSANISSS PKGSPSSSRK SGTSCPSSKN SSPNSSPRTL 1210 1220 1230 1240 1250 1260 GRSKGRLRLP QIGSKNKPSS SKKNLDASKE NGAGQICELA DALSRGHMRG GSQPELVTPQ 1270 1280 1290 1300 1310 1320 DHEVALANGF LYEHEACGNG CGDGYSNGQL GNHSEEDSTD DQREDTHIKP IYNLYAISCH 1330 1340 1350 1360 1370 1380 SGILSGGHYI TYAKNPNCKW YCYNDSSCEE LHPDEIDTDS AYILFYEQQG IDYAQFLPKI 1390 1400 DGKKMADTSS TDEDSESDYE KYSMLQ
	Isoform 2 (213(ORF2)). Checksum: A660606208ABD9EB	FASTA	1,089	121,943
	10 20 30 40 50 60 MPQRLPHARQ HTPLPLGSAD YRRVVSVRPQ GPHRDPKDSR DAAKREQGSL APRPVPASRG 70 80 90 100 110 120 GKTLCKGYRQ APPGPPAQFQ RPICSASPPW ASRFSTPCPG GAVREDTYPV GTQGVPSLAL 130 140 150 160 170 180 AQGGPQGSWR FLEWKSMPRL PTDLDIGGPW FPHYDFEWSC WVRAISQEDQ LATCWQAEHC 190 200 210 220 230 240 GEVHNKDMSW PEEMSFTANS SKIDRQKVPT EKGATGLSNL GNTCFMNSSI QCVSNTQPLT 250 260 270 280 290 300 QYFISGRHLY ELNRTNPIGM KGHMAKCYGD LVQELWSGTQ KSVAPLKLRR TIAKYAPKFD 310 320 330 340 350 360 GFQQQDSQEL LAFLLDGLHE DLNRVHEKPY VELKDSDGRP DWEVAAEAWD NHLRRNRSII 370 380 390 400 410 420 VDLFHGQLRS QVKCKTCGHI SVRFDPFNFL SLPLPMDSYM DLEITVIKLD GTTPVRYGLR 430 440 450 460 470 480 LNMDEKYTGL KKQLRDLCGL NSEQILLAEV HDSNIKNFPQ DNQKVQLSVS GFLCAFEIPV 490 500 510 520 530 540 PSSPISASSP TQIDFSSSPS TNGMFTLTTN GDLPKPIFIP NGMPNTVVPC GTEKNFTNGM 550 560 570 580 590 600 VNGHMPSLPD SPFTGYIIAV HRKMMRTELY FLSPQENRPS LFGMPLIVPC TVHTRKKDLY 610 620 630 640 650 660 DAVWIQVSWL ARPLPPQEAS IHAQDRDNCM GYQYPFTLRV VQKDGNSCAW CPQYRFCRGC 670 680 690 700 710 720 KIDCGEDRAF IGNAYIAVDW HPTALHLRYQ TSQERVVDKH ESVEQSRRAQ AEPINLDSCL 730 740 750 760 770 780 RAFTSEEELG ESEMYYCSKC KTHCLATKKL DLWRLPPFLI IHLKRFQFVN DQWIKSQKIV 790 800 810 820 830 840 RFLRESFDPS AFLVPRDPAL CQHKPLTPQG DELSKPRILA REVKKVDAQS SAGKEDMLLS 850 860 870 880 890 900 KSPSSLSANI SSSPKGSPSS SRKSGTSCPS SKNSSPNSSP RTLGRSKGRL RLPQIGSKNK 910 920 930 940 950 960 PSSSKKNLDA SKENGAGQIC ELADALSRGH MRGGSQPELV TPQDHEVALA NGFLYEHEAC 970 980 990 1000 1010 1020 GNGCGDGYSN GQLGNHSEED STDDQREDTH IKPIYNLYAI SCHSGILSGG HYITYAKNPN 1030 1040 1050 1060 1070 1080 CKWYCYNDSS CEELHPDEID TDSAYILFYE QQGIDYAQFL PKIDGKKMAD TSSTDEDSES DYEKYSMLQ
	Isoform 3 (210(ORF1)) (oncTre210p). Checksum: 6D5D93D2CE65D879	FASTA	786	89,577
	10 20 30 40 50 60 MDMVENADSL QAQERKDILM KYDKGHRAGL PEDKGPEPVG INSSIDRFGI LHETELPPVT 70 80 90 100 110 120 AREAKKIRRE MTRTSKWMEM LGEWETYKHS SKLIDRVYKG IPMNIRGPVW SVLLNIQEIK 130 140 150 160 170 180 LKNPGRYQIM KERGKRSSEH IHHIDLDVRT TLRNHVFFRD RYGAKQRELF YILLAYSEYN 190 200 210 220 230 240 PEVGYCRDLS HITALFLLYL PEEDAFWALV QLLASERHSL PGFHSPNGGT VQGLQDQQEH 250 260 270 280 290 300 VVPKSQPKTM WHQDKEGLCG QCASLGCLLR NLIDGISLGL TLRLWDVYLV EGEQVLMPIT 310 320 330 340 350 360 SIALKVQQKR LMKTSRCGLW ARLRNQFFDT WAMNDDTVLK HLRASTKKLT RKQGDLPPPA 370 380 390 400 410 420 KREQGSLAPR PVPASRGGKT LCKGYRQAPP GPPAQFQRPI CSASPPWASR FSTPCPGGAV 430 440 450 460 470 480 REDTYPVGTQ GVPSLALAQG GPQGSWRFLE WKSMPRLPTD LDIGGPWFPH YDFEWSCWVR 490 500 510 520 530 540 AISQEDQLAT CWQAEHCGEV HNKDMSWPEE MSFTANSSKI DRQKVPTEKG ATGLSNLGNT 550 560 570 580 590 600 CFMNSSIQCV SNTQPLTQYF ISGRHLYELN RTNPIGMKGH MAKCYGDLVQ ELWSGTQKSV 610 620 630 640 650 660 APLKLRRTIA KYAPKFDGFQ QQDSQELLAF LLDGLHEDLN RVHEKPYVEL KDSDGRPDWE 670 680 690 700 710 720 VAAEAWDNHL RRNRSIIVDL FHGQLRSQVK CKTCGHISVR FDPFNFLSLP LPMDSYMDLE 730 740 750 760 770 780 ITVIKLDGTT PVRYGLRLNM DEKYTGLKKQ LRDLCGLNSE QILLAEVHDS NIKISPLHHL QMECSP

References

[1]	"A novel transcriptional unit of the tre oncogene widely expressed in human cancer cells." Nakamura T., Hillova J., Mariage-Samson R., Onno M., Huebner K., Cannizzaro L.A., Boghosian-Sell L., Croce C.M., Hill M. Oncogene 7:733-741(1992) [PubMed: 1565468] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3), TISSUE SPECIFICITY, VARIANTS ARG-475 AND GLN-912. Tissue: Ewing sarcoma.
[2]	"The Tre2 (USP6) oncogene is a hominoid-specific gene." Paulding C.A., Ruvolo M., Haber D.A. Proc. Natl. Acad. Sci. U.S.A. 100:2507-2511(2003) [PubMed: 12604796] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1), ALTERNATIVE SPLICING, TISSUE SPECIFICITY, DISCUSSION OF TRE2 EVOLUTION.
[3]	"The yeast DOA4 gene encodes a deubiquitinating enzyme related to a product of the human tre-2 oncogene." Papa F.R., Hochstrasser M. Nature 366:313-319(1993) [PubMed: 8247125] [Abstract] Cited for: CHARACTERIZATION.
[4]	"Expression in a RabGAP yeast mutant of two human homologues, one of which is an oncogene." Bizimungu C., De Neve N., Burny A., Bach S., Bontemps F., Portetelle D., Vandenbol M. Biochem. Biophys. Res. Commun. 310:498-504(2003) [PubMed: 14521938] [Abstract] Cited for: MUTAGENESIS OF THR-150 AND ARG-187.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases
EMBL GenBank DDBJ	X63546 mRNA. Translation: CAA45108.1. X63547 mRNA. Translation: CAA45111.1. AY143550 mRNA. Translation: AAN38838.1. AY163314 Genomic DNA. Translation: AAO21348.1.
IPI	IPI00423562. IPI00423563. IPI00423565.
PIR	S57867. S22158. S57868. S22155. S57874.
RefSeq	NP_004496.2.
UniGene	Hs.448851
3D structure databases
SMR	P35125. Positions 73-325, 528-712.
ModBase	Search...
Protein-protein interaction databases
IntAct	P35125. 5 interactions.
STRING	P35125.
Protein family/group databases
MEROPS	C19.009.
PTM databases
PhosphoSite	P35125.
Proteomic databases
PRIDE	P35125.
Genome annotation databases
Ensembl	ENST00000250066; ENSP00000250066; ENSG00000129204; Homo sapiens. [Genome view] ENST00000304328; ENSP00000305473; ENSG00000129204; Homo sapiens. [Genome view]
GeneID	9098.
KEGG	hsa:9098.
UCSC	uc002gau.1. human. uc010ckz.1. human.
Organism-specific databases
CTD	9098.
GeneCards	GC17P004972.
H-InvDB	HIX0005679. HIX0021760.
HGNC	HGNC:12629. USP6.
HPA	HPA011742.
MIM	604334. gene.
PharmGKB	PA27529.
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG18311.
HOVERGEN	P35125.
InParanoid	P35125.
OMA	SCAWCPQ.
OrthoDB	EOG94XN5F.
PhylomeDB	P35125.
Enzyme and pathway databases
BRENDA	3.1.2.15. 247.
Pathway_Interaction_DB	arf6cyclingpathway. Arf6 signaling events.
Gene expression databases
ArrayExpress	P35125.
Bgee	P35125.
CleanEx	HS_USP6.
Genevestigator	P35125.
GermOnline	ENSG00000129204. Homo sapiens.
Family and domain databases
InterPro	IPR018200. Pept_C19ubi-hydrolase_C_CS. IPR001394. Peptidase_C19. IPR000195. RabGAP_TBC. [Graphical view]
Pfam	PF00566. TBC. 1 hit. PF00443. UCH. 1 hit. [Graphical view]
SMART	SM00164. TBC. 1 hit. [Graphical view]
PROSITE	PS50086. TBC_RABGAP. 1 hit. PS00972. UCH_2_1. 1 hit. PS00973. UCH_2_2. 1 hit. PS50235. UCH_2_3. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	34099.
SOURCE	Search...

Entry information

Entry name

UBP6_HUMAN

Accession

Primary (citable) accession number: P35125
Secondary accession number(s): Q15634, Q86WP6, Q8IWT4

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1994
Last sequence update:	July 19, 2004
Last modified:	January 19, 2010
This is version 81 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

Disclaimer

Any 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.