ELM Details - LIG_USP7

LIG_USP7_2

Functional site class:	USP7 binding motif
Functional site description:	USP7, also known as HAUSP, is a deubiquitinating enzyme which cleaves ubiquitin moieties from its substrates. The USP7-mediated deubiquitination of P53, Mdm2 and USP7 inhibition by the herpesviral proteins EBNA1 and ICP0 shows its importance in the regulation of cell survival pathways and controlling key cellular processes important for viral infection. The N-terminal TRAF-like domain of USP7 is responsible for substrate recognition and nuclear localization while the catalytic core domain is required for the deubiquitinating activity.
ELM(s):	LIG_USP7_2, LIG_USP7_1
LIG_USP7_2 description:	Targeting motif found in a USP7 binding protein, docking to the NTD domain. The USP7 N-terminal domain is a TRAF-like domain but with different sequence specificity to the classical TRAF domain. The motif identified in EBNA1 recognizes the same surface groove in USP7 as the p53 and MDM2 motifs, but requires a different description. The EBNA1 motif is high affinity but currently only this single example is known on which to base the motif. From the complex structure, core residues for the motif are P.E..S where the E substitutes for the P in the alternative motif (The E reaches to a complementarily-charged residue). It is not clear if there are cellular USP7 inhibitor (or substrate) proteins with the viral-like motif although this seems quite feasible.
Pattern:	P.E[^P].S[^P]
Present in taxon(s):	Eukaryota
Not represented in taxon(s):

See instances for LIG_USP7_2

Abstract

Deubiquitinating enzymes (DUBs) are a family of thiol- and metallo-proteases specialized in the processing of ubiquitin and ubiquitin-like proteins (Amerik AY, Hochstrasser M, 2004).USP7 is a prominent member of the ubiquitin-specific protease (USP) subfamily. It has also been named as Herpesvirus Associated Ubiquitin–Specific Protease (HAUSP) since it was first identified as a protein associated with ICP0, a regulatory protein of the herpes simplex virus which directs P53 to proteasomal destruction (Everett et al., 1997). USP7 is involved in the regulation of stress response pathways, epigenetic silencing, cell survival pathway and the progress of infections by DNA viruses(Amerik AY and Hochstrasser M,2004).
USP7 comprises four domains. The N-terminal domain (NTD), which forms an eight-stranded antiparallel beta-sandwitch (Sheng et al., 2005), is a divergent member of the linear motif binding TRAF domain family (Pfam:PF00917) – see the LIG_TRAF ELM entries. The USP7 NTD is known to interact with peptide ligand motifs in P53 and MDM2, enabling their deubiquitination. The NTD domain can also interact with the EBV protein EBNA1 to block USP7 activity and promote P53 elimination, as part of the mechanism to immortalise B-Cells (Saridakis et al., 2005). Besides the NTD, two C-terminal domains also mediate protein-protein interactions. For example, the HSV ICP0 protein mentioned above binds to one of the C-terminal domains. The USP7 catalytic domain responsible for the deubiquitination of substrate proteins is distinct from these three protein targeting domains.
Structural and mutational binding studies revealed that short peptides in disordered regions of both p53 and MDM2 interact with the same location on the USP7 NTD domain in a mutually exclusive manner. They have related motifs based on a conserved P..S core, but the MDM2 variant binds USP7 with a much higher affinity possibly required for the role of USP7 in regulating p53 destruction by the MDM2 pathway (see ELM:LIG_MDM2). The high affinity EBNA site approximates to a P.E..S motif. The Ser is equivalent in both motif classes and is suitable to be regulated by phosphorylation as a PhosphoSer is structurally disallowed in the complex. However proline-directed kinases (MapKs, CDKs, Hipk2 etc.) could not phosphorylate these sites as Pro is structurally disallowed in the position following the Ser.

Selected references

Cheon KW, Baek KH

HAUSP as a therapeutic target for hematopoietic tumors (review).

Int J Oncol 2006 May;28(5) : 1209-15.

PMID: 16596237

Holowaty MN, Sheng Y, Nguyen T, Arrowsmith C, Frappier L

Protein interaction domains of the ubiquitin-specific protease, USP7/HAUSP.

J Biol Chem 2003 Nov 28;278(48) : 47753-61.

PMID: 14506283

Hu M, Gu L, Li M, Jeffrey PD, Gu W, Shi Y

Structural basis of competitive recognition of p53 and MDM2 by HAUSP/USP7: implications for the regulation of the p53-MDM2 pathway.

PLoS Biol 2006 Feb;4(2) : e27.

PMID: 16402859

Hu M, Li P, Li M, Li W, Yao T, Wu JW, Gu W, Cohen RE, Shi Y

Crystal structure of a UBP-family deubiquitinating enzyme in isolation and in complex with ubiquitin aldehyde.

Cell 2002 Dec 27;111(7) : 1041-54.

PMID: 12507430

Saridakis V, Sheng Y, Sarkari F, Holowaty MN, Shire K, Nguyen T, Zhang RG, Liao J, Lee W, Edwards AM, Arrowsmith CH, Frappier L

Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein-Barr nuclear antigen 1 implications for EBV-mediated immortalization.

Mol Cell 2005 Apr 1;18(1) : 25-36.

PMID: 15808506

Sheng Y, Saridakis V, Sarkari F, Duan S, Wu T, Arrowsmith CH, Frappier L

Molecular recognition of p53 and MDM2 by USP7/HAUSP.

Nat Struct Mol Biol 2006 Mar;13(3) : 285-91.

PMID: 16474402

This ELM has been assigned the following Gene Ontology (GO) terms for biological process, cellular component and molecular function.

Biological Process

  protein deubiquitination

GO:0016579

Cellular Component

  nucleus

GO:0005634

Molecular Function

  Peptide binding

GO:0042277

  ubiquitin-specific protease activity

GO:0004843

Instances for LIG_USP7_2

Sequence	Position	Subsequence (Click for evidence information)	PDB	Gene Name	Protein Description	Organism
EBNA1_EBV	442-448	GPADDPGEGPSTGPRGQG	1YY6	Name=EBNA1; ORFNames=BKRF1;	Epstein-Barr nuclear antigen 1 (EBV nuclear antigen 1) (EBNA-1).	Epstein-Barr virus (strain B95-8) (HHV-4) (Human herpesvirus 4).