Reviewed, UniProtKB/Swiss-Prot Q93009 (UBP7_HUMAN)

Names and origin

Protein names

Recommended name:
    Ubiquitin carboxyl-terminal hydrolase 7
    EC=3.1.2.15
Alternative name(s):
    Ubiquitin thioesterase 7
    Ubiquitin-specific-processing protease 7
    Deubiquitinating enzyme 7
    Herpesvirus-associated ubiquitin-specific protease

Gene names

Name:	USP7
Synonyms:	HAUSP

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	1102 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Cleaves ubiquitin fusion protein substrates. Deubiquitinates TP53/p53 and MDM2 and strongly stabilizes TP53 even in the presence of excess MDM2, and also induces TP53-dependent cell growth repression and apoptosis. Ref.6 Ref.7
Catalytic activity	Ubiquitin C-terminal thioester + H2O = ubiquitin + a thiol.
Enzyme regulation	Inhibited by N-ethyl-maleimide (NEM) and divalent cations. Tolerates high concentrations of NaCl but is inhibited at concentrations of 195 mM and higher. Ref.7
Subunit structure	Monomer. Interacts with TP53, MDM2 and UBXN6. Interacts with herpesvirus 1 trans-acting transcriptional protein ICP0/VMW110 and Epstein-Barr virus EBNA1. EBNA1 shows a 10-fold higher affinity than TP53 and can compete with it for USP7 binding. Binding to VMW110 may modulate the substrate specificity or activity of USP7 to stabilize viral proteins. Interacts with ATXN1 and the strength of interaction is influenced by the length of the poly-Gln region in ATXN1. A weaker interaction seen with mutants having longer poly-Gln regions. Ref.6 Ref.7 Ref.5 Ref.9 Ref.12 Ref.13 Ref.14 Ref.15
Subcellular location	Nucleus. Note: Present in a minority of ND10 nuclear bodies. Association with VMW110 at early times of infection leads to an increased proportion of USP7-containing ND10. Colocalizes with ATXN1 in the nucleus. Ref.5
Tissue specificity	Widely expressed.
Post-translational modification	Polyneddylated By similarity. Polyubiquitinated By similarity.
Sequence similarities	Belongs to the peptidase C19 family. Contains 1 MATH domain.
Biophysicochemical properties	pH dependence: Active from pH 7.0 to 9.5.

Ontologies

Keywords
Biological process	Host-virus interaction Ubl conjugation pathway
Cellular component	Nucleus
Molecular function	Hydrolase Protease Thiol protease
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Direct protein sequencing
Gene Ontology (GO)
Biological process	interspecies interaction between organisms Inferred from electronic annotation. Source: UniProtKB-KW protein deubiquitination Ref.6 Inferred from mutant phenotype. Source: UniProtKB ubiquitin-dependent protein catabolic process Inferred from electronic annotation. Source: InterPro
Cellular component	nucleus Ref.5 Inferred from direct assay. Source: UniProtKB
Molecular function	cysteine-type endopeptidase activity Traceable author statement. Source: ProtInc protein C-terminus binding Ref.5 Inferred from physical interaction. Source: UniProtKB ubiquitin thiolesterase activity Inferred from electronic annotation. Source: EC ubiquitin-specific protease activity Ref.6 Inferred from mutant phenotype. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
DAXX	Q9UER7	4	EBI-302474,EBI-77321
EBNA1	P03211	3	EBI-302474,EBI-996522	From a different organism.
MAGEB2	O15479	1	EBI-302474,EBI-1057615
MDM2	Q00987	4	EBI-302474,EBI-389668
RNPS1	Q15287	1	EBI-302474,EBI-395959
RUVBL2	Q9Y230	1	EBI-302474,EBI-352939
TBCB	Q99426	1	EBI-302474,EBI-764356
TP53	P04637	4	EBI-302474,EBI-366083

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 1102

1102

Ubiquitin carboxyl-terminal hydrolase 7

PRO_0000080626

Regions

Domain

68 – 195

128

MATH

Region

53 – 208

156

Interaction with TP53, MDM2 and EBNA1

Region

622 – 801

180

Interaction with ICP0/VMW110

Compositional bias

4 – 10

7

Poly-Gln

Sites

Active site

223

1

Active site

456

1

Active site

464

1

Amino acid modifications

Modified residue

18

1

Phosphoserine Ref.8 Ref.10

Modified residue

963

1

Phosphoserine Ref.10

Experimental info

Mutagenesis

164

1

D → A: Decreased binding to TP53 and MDM2. Ref.15

Mutagenesis

165

1

W → A: Loss of binding to TP53 and MDM2. Ref.15

Mutagenesis

223

1

C → A: Complete loss of activity. Ref.6 Ref.12

Mutagenesis

223

1

C → S: No effect on TP53 binding but is defective in deubiquitinating p53. Ref.6 Ref.12

Mutagenesis

456

1

H → A: Complete loss of activity. Ref.12

Mutagenesis

464

1

H → A: Complete loss of activity. Ref.12

Sequence conflict

201

1

H → I AA sequence Ref.1

Sequence conflict

205

1

W → P AA sequence Ref.1

Sequence conflict

207

1

S → Q AA sequence Ref.1

Sequence conflict

1045

1

M → T in CAA96580. Ref.1

Sequence conflict

1066

1

Q → T AA sequence Ref.1

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

1102

Helix Strand Turn

Details...

Beta strand

67 – 77

11

Helix

78 – 80

3

Beta strand

90 – 92

3

Beta strand

95 – 104

10

Beta strand

114 – 122

9

Beta strand

131 – 140

10

Helix

146 – 148

3

Beta strand

150 – 159

10

Beta strand

164 – 172

9

Helix

173 – 176

4

Turn

179 – 181

3

Beta strand

188 – 197

10

Beta strand

201 – 203

3

Beta strand

210 – 212

3

Helix

223 – 233

11

Helix

236 – 243

8

Turn

252 – 254

3

Helix

256 – 269

14

Helix

277 – 282

6

Helix

287 – 291

5

Helix

296 – 311

16

Turn

315 – 318

4

Helix

319 – 324

6

Beta strand

326 – 337

12

Beta strand

340 – 353

14

Helix

360 – 367

8

Beta strand

371 – 373

3

Helix

375 – 377

3

Beta strand

389 – 397

9

Beta strand

400 – 407

8

Beta strand

409 – 412

4

Turn

413 – 416

4

Beta strand

417 – 420

4

Beta strand

429 – 432

4

Helix

434 – 436

3

Beta strand

437 – 439

3

Beta strand

447 – 459

13

Beta strand

462 – 469

8

Beta strand

473 – 475

3

Beta strand

478 – 481

4

Beta strand

484 – 487

4

Helix

490 – 493

4

Helix

495 – 497

3

Turn

507 – 510

4

Beta strand

511 – 520

10

Helix

521 – 523

3

Helix

524 – 527

4

Helix

533 – 535

3

Helix

538 – 545

8

Helix

547 – 550

4

Sequences

	Sequence		Length	Mass (Da)
	Q93009-1 [UniParc]. Last modified November 4, 2008. Version 2. Checksum: F1A5A5C421396E45	FASTA	1,102	128,302
	10 20 30 40 50 60 MNHQQQQQQQ KAGEQQLSEP EDMEMEAGDT DDPPRITQNP VINGNVALSD GHNTAEEDME 70 80 90 100 110 120 DDTSWRSEAT FQFTVERFSR LSESVLSPPC FVRNLPWKIM VMPRFYPDRP HQKSVGFFLQ 130 140 150 160 170 180 CNAESDSTSW SCHAQAVLKI INYRDDEKSF SRRISHLFFH KENDWGFSNF MAWSEVTDPE 190 200 210 220 230 240 KGFIDDDKVT FEVFVQADAP HGVAWDSKKH TGYVGLKNQG ATCYMNSLLQ TLFFTNQLRK 250 260 270 280 290 300 AVYMMPTEGD DSSKSVPLAL QRVFYELQHS DKPVGTKKLT KSFGWETLDS FMQHDVQELC 310 320 330 340 350 360 RVLLDNVENK MKGTCVEGTI PKLFRGKMVS YIQCKEVDYR SDRREDYYDI QLSIKGKKNI 370 380 390 400 410 420 FESFVDYVAV EQLDGDNKYD AGEHGLQEAE KGVKFLTLPP VLHLQLMRFM YDPQTDQNIK 430 440 450 460 470 480 INDRFEFPEQ LPLDEFLQKT DPKDPANYIL HAVLVHSGDN HGGHYVVYLN PKGDGKWCKF 490 500 510 520 530 540 DDDVVSRCTK EEAIEHNYGG HDDDLSVRHC TNAYMLVYIR ESKLSEVLQA VTDHDIPQQL 550 560 570 580 590 600 VERLQEEKRI EAQKRKERQE AHLYMQVQIV AEDQFCGHQG NDMYDEEKVK YTVFKVLKNS 610 620 630 640 650 660 SLAEFVQSLS QTMGFPQDQI RLWPMQARSN GTKRPAMLDN EADGNKTMIE LSDNENPWTI 670 680 690 700 710 720 FLETVDPELA ASGATLPKFD KDHDVMLFLK MYDPKTRSLN YCGHIYTPIS CKIRDLLPVM 730 740 750 760 770 780 CDRAGFIQDT SLILYEEVKP NLTERIQDYD VSLDKALDEL MDGDIIVFQK DDPENDNSEL 790 800 810 820 830 840 PTAKEYFRDL YHRVDVIFCD KTIPNDPGFV VTLSNRMNYF QVAKTVAQRL NTDPMLLQFF 850 860 870 880 890 900 KSQGYRDGPG NPLRHNYEGT LRDLLQFFKP RQPKKLYYQQ LKMKITDFEN RRSFKCIWLN 910 920 930 940 950 960 SQFREEEITL YPDKHGCVRD LLEECKKAVE LGEKASGKLR LLEIVSYKII GVHQEDELLE 970 980 990 1000 1010 1020 CLSPATSRTF RIEEIPLDQV DIDKENEMLV TVAHFHKEVF GTFGIPFLLR IHQGEHFREV 1030 1040 1050 1060 1070 1080 MKRIQSLLDI QEKEFEKFKF AIVMMGRHQY INEDEYEVNL KDFEPQPGNM SHPRPWLGLD 1090 1100 HFNKAPKRSR YTYLEKAIKI HN

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A novel ubiquitin-specific protease is dynamically associated with the PML nuclear domain and binds to a herpesvirus regulatory protein." Everett R.D., Meredith M., Orr A., Cross A., Kathoria M., Parkinson J. EMBO J. 16:566-577(1997) [PubMed: 9034339] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE. Tissue: Mammary cancer.
[2]	Erratum Everett R.D., Meredith M., Orr A., Cross A., Kathoria M., Parkinson J. EMBO J. 16:1519-1530(1997) [PubMed: 9130697] [Abstract]
[3]	"The sequence and analysis of duplication-rich human chromosome 16." Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J. , Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J., Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D., Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M., Rubin E.M., Pennacchio L.A. Nature 432:988-994(2004) [PubMed: 15616553] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"USP7, a ubiquitin-specific protease, interacts with ataxin-1, the SCA1 gene product." Hong S., Kim S.J., Ka S., Choi I., Kang S. Mol. Cell. Neurosci. 20:298-306(2002) [PubMed: 12093161] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 705-1102, SUBCELLULAR LOCATION, INTERACTION WITH ATXN1.
[6]	"Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization." Li M., Chen D., Shiloh A., Luo J., Nikolaev A.Y., Qin J., Gu W. Nature 416:648-653(2002) [PubMed: 11923872] [Abstract] Cited for: FUNCTION, INTERACTION WITH TP53, MUTAGENESIS OF CYS-223.
[7]	"Protein interaction domains of the ubiquitin-specific protease, USP7/HAUSP." Holowaty M.N., Sheng Y., Nguyen T., Arrowsmith C., Frappier L. J. Biol. Chem. 278:47753-47761(2003) [PubMed: 14506283] [Abstract] Cited for: FUNCTION, SUBUNIT, BIOPHYSICOCHEMICAL PROPERTIES, ENZYME REGULATION, INTERACTION WITH HERPESVIRUS 1 TRANS-ACTING TRANSCRIPTIONAL PROTEIN ICP0/VMW110 AND EBV EBNA1.
[8]	"Large-scale characterization of HeLa cell nuclear phosphoproteins." Beausoleil S.A., Jedrychowski M., Schwartz D., Elias J.E., Villen J., Li J., Cohn M.A., Cantley L.C., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 101:12130-12135(2004) [PubMed: 15302935] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-18, MASS SPECTROMETRY. Tissue: Epithelium.
[9]	"AAA ATPase p97 and adaptor UBXD1 suppress MDM2 ubiquitination and degradation and promote constitutive p53 turnover." Zweitzig D.R., Shcherbik N., Haines D.S. Mol. Biol. Cell 19:5029-5029(2008) [PubMed: 18768758] [Abstract] Cited for: INTERACTION WITH UBXN6.
[10]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-18 AND SER-963, MASS SPECTROMETRY.
[11]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[12]	"Crystal structure of a UBP-family deubiquitinating enzyme in isolation and in complex with ubiquitin aldehyde." Hu M., Li P., Li M., Li W., Yao T., Wu J.-W., Gu W., Cohen R.E., Shi Y. Cell 111:1041-1054(2002) [PubMed: 12507430] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 208-560 IN COMPLEX WITH UBIQUITIN, MUTAGENESIS OF CYS-223; HIS-456 AND HIS-464, INTERACTION WITH TP53.
[13]	"Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein-Barr nuclear antigen 1 implications for EBV-mediated immortalization." Saridakis V., Sheng Y., Sarkari F., Holowaty M.N., Shire K., Nguyen T., Zhang R.G., Liao J., Lee W., Edwards A.M., Arrowsmith C.H., Frappier L. Mol. Cell 18:25-36(2005) [PubMed: 15808506] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 54-205 IN COMPLEX WITH EBNA1, INTERACTION WITH EBV EBNA1.
[14]	"Structural basis of competitive recognition of p53 and MDM2 by HAUSP/USP7: implications for the regulation of the p53-MDM2 pathway." Hu M., Gu L., Li M., Jeffrey P.D., Gu W., Shi Y. PLoS Biol. 4:228-239(2006) [PubMed: 16402859] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS) OF 43-560 IN COMPLEX WITH TP53 AND MDM2, INTERACTION WITH TP53 AND MDM2.
[15]	"Molecular recognition of p53 and MDM2 by USP7/HAUSP." Sheng Y., Saridakis V., Sarkari F., Duan S., Wu T., Arrowsmith C.H., Frappier L. Nat. Struct. Mol. Biol. 13:285-291(2006) [PubMed: 16474402] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 54-205 IN COMPLEX WITH TP53 AND MDM2, INTERACTION WITH TP53 AND MDM2, MUTAGENESIS OF ASP-164 AND TRP-165.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases

EMBLGenBankDDBJ

Z72499 mRNA. Translation: CAA96580.1.
AC022167 Genomic DNA. No translation available.
CH471112 Genomic DNA. Translation: EAW85194.1.

IPI

IPI00003965.

RefSeq

NP_003461.2.

UniGene

Hs.706830

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1NB8	X-ray	2.30	A/B	208-560	[»]
1NBF	X-ray	2.30	A/B/E	208-560	[»]
1YY6	X-ray	1.70	A	54-205	[»]
1YZE	X-ray	2.00	A/B/C	54-205	[»]
2F1W	X-ray	1.65	A	53-206	[»]
2F1X	X-ray	2.30	A/B	53-200	[»]
2F1Y	X-ray	1.70	A	53-198	[»]
2F1Z	X-ray	3.20	A/B	43-560	[»]
2FOJ	X-ray	1.60	A	54-205	[»]
2FOO	X-ray	2.20	A	54-205	[»]
2FOP	X-ray	2.10	A	54-205	[»]

ModBase

Search...

Protein-protein interaction databases

DIP

DIP:29053N.

IntAct

Q93009. 37 interactions.

Protein family/group databases

MEROPS

C19.016.

PTM databases

PhosphoSite

Q93009.

Proteomic databases

PRIDE

Q93009.

Genome annotation databases

Ensembl

ENSG00000187555. Homo sapiens. [Contig view]

GeneID

7874.

KEGG

hsa:7874.

Organism-specific databases

GeneCards

GC16M008894.

H-InvDB

HIX0038590.

HGNC

HGNC:12630. USP7.

HPA

CAB008108.
HPA015641.

MIM

602519. gene.

PharmGKB

PA27530.

GenAtlas

Search...

Phylogenomic databases

HOVERGEN

Q93009.

Enzyme and pathway databases

BRENDA

3.1.2.15. 247.

Pathway_Interaction_DB

foxopathway. FoxO family signaling.

Gene expression databases

ArrayExpress

Q93009.

Bgee

Q93009.

CleanEx

HS_USP7.

GermOnline

ENSG00000187555. Homo sapiens.

Family and domain databases

InterPro

IPR002083. MATH.
IPR018200. Pept_C19ubi-hydrolase_C_CS.
IPR001394. Peptidase_C19.
[Graphical view]

Pfam

PF00917. MATH. 1 hit.
PF00443. UCH. 1 hit.
[Graphical view]

SMART

SM00061. MATH. 1 hit.
[Graphical view]

PROSITE

PS50144. MATH. 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

30332.

SOURCE

Search...

Entry information

Entry name

UBP7_HUMAN

Accession

Primary (citable) accession number: Q93009
Secondary accession number(s): A6NMY8

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	November 4, 2008
Last modified:	July 7, 2009
This is version 102 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)