The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Accession:
Functional site class:
USP7 binding motif
Functional site description:
USP7, also known as HAUSP, is a deubiquitinating enzyme that cleaves ubiquitin moieties from its substrates. The USP7-mediated deubiquitination of p53, MDM2 and USP7 inhibition by the herpes viral proteins EBNA1 and ICP0 shows its importance in the regulation of cell survival pathways and in controlling key cellular processes important for viral infection. The N-terminal MATH domain of USP7 is responsible for substrate recognition and nuclear localization while the catalytic core domain is required for the deubiquitinating activity. The C-terminal Ubl domain is responsible for several USP7 substrate interactions, including ICP0, GMPS, DNMT1 and UHRF1 leading to substrate stabilisation, USP7 translocation or activation
ELMs with same func. site: DOC_USP7_MATH_1  DOC_USP7_MATH_2  DOC_USP7_UBL2_3 
ELM Description:
Targeting motif found in USP7 substrates, docking to the MATH domain. The USP7 MATH domain is a TRAF-like domain but with different sequence specificity to the classical TRAF domain. The motif identified in p53 and MDM2 recognises the same surface groove in USP7. But MDM2s make more extensive contacts than p53, leading to stronger affinity. The motif identified in these proteins can therefore be categorised as either a lower affinity motif or high affinity motif, depending on the extent of contact. The general pattern of the motif is a simple P..S and will have frequent matches in cellular proteins but it is not clear how numerous are the USP7 substrates.
Pattern: [PA][^P][^FYWIL]S[^P]
Pattern Probability: 0.0123885
Present in taxon: Eukaryota
Interaction Domain:
MATH (PF00917) MATH domain (Stochiometry: 1 : 1)
PDB Structure: 2FOJ
o See 10 Instances for DOC_USP7_MATH_1
o Abstract
The DUB ubiquitin specific protease 7 (USP7) is a cysteine protease that was first identified as a binding partner for the Herpes simplex viral protein infected cell protein 0 (ICP0) which is why it is also called HAUSP (herpes simplex virus associated ubiquitin-specific protease). USP7 is responsible for the deubiquitination of many cellular proteins, thereby playing an important role in regulating biological processes including tumour suppression, immune responses, DNA repair and epigenetic control. (Nicholson,2011) Next to its catalytic domain, USP7 contains a N-terminal MATH domain and five C-terminal ubiquitin-like domains (UBLs) forming the HUBL domain (Faesen,2012).
One of the most important USP7-interactions is the regulation of the tumour suppressor p53 through the stabilisation of MDM2 (HDM2), an E3 ligase which ubiquitinates p53 and thereby mediates its degradation (Nicholson,2011). MDM2 and p53 contain at least two binding sites for USP7, one on the N-terminal USP7 MATH domain, responsible for its nuclear localisation, and one on the C-terminal USP7 Ubl123 domain responsible for MDM2-catalysed p53 deubiquitination. 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 MATH domain in a mutually exclusive manner (Ma,2010).
The motifs responsible for N-terminal USP7 binding are based on a conserved P..S core, although 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 (ELM: DOC_USP7_MATH_1, DOC_USP7_MATH_2) The motifs responsible for C-terminal USP7 interactions of MDM2 and p53 are still to be characterised. The MATH 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,2005) 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 phospho Ser 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.
The viral E3 ligase ICP0 binds to the C-terminal USP7 Ubl2 domain between amino acids 599-801 leading to a promiscuous activation of gene expression and the destruction of multiple cellular proteins, thereby overcoming the intrinsic cellular antiviral response (4WPH, 4WPI). The motif is characterised as a conserved K…K (DOC_USP7_Ubl2_3) core although the binding event might be regulated by cooperative binging of the N-terminal motif. This might explain how despite its low discrimination this binding event is able to maintain specificity. GMPS and UHRF1 also bind to the same USP7 binding pocket as ICP0, although this fact is still to be confirmed via crystal structures of these interactions. GMPS is involved in p53 regulation and the UHRF1-DNMT1-USP7 complex affects DNA methylation. (Pfoh,2015) DNMT1 was also shown to C-terminally bind USP7, using the same binding motif as ICP0 (4YOC, Cheng,2015).
o 7 selected references:

o 4 GO-Terms:

o 10 Instances for DOC_USP7_MATH_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
O15151 MDM4
MDM4_HUMAN
470 474 CARRLKKAGASCPICKKEIQ TN 1 Homo sapiens (Human)
O15151 MDM4
MDM4_HUMAN
388 392 ENSKLFDPCNSVEFLDLAHS TN 1 Homo sapiens (Human)
Q00987 MDM2
MDM2_HUMAN
385 389 NDDKITQASQSQESEDYSQP TN 1 Homo sapiens (Human)
Q00987 MDM2
MDM2_HUMAN
397 401 ESEDYSQPSTSSSIIYSSQE TP 3 Homo sapiens (Human)
1 
O15151 MDM4
MDM4_HUMAN
398 402 SVEFLDLAHSSESQETISSM TP 5 Homo sapiens (Human)
1 
O15151 MDM4
MDM4_HUMAN
8 12 MTSFSTSAQCSTSDSACRIS TP 4 Homo sapiens (Human)
1 
Q00987 MDM2
MDM2_HUMAN
226 230 PSNPDLDAGVSEHSGDWLDQ TP 2 Homo sapiens (Human)
Q00987 MDM2
MDM2_HUMAN
147 151 QELQEEKPSSSHLVSRPSTS TP 5 Homo sapiens (Human)
P04637 TP53
P53_HUMAN
364 368 KEPGGSRAHSSHLKSKKGQS TP 3 Homo sapiens (Human)
P04637 TP53
P53_HUMAN
359 363 DAQAGKEPGGSRAHSSHLKS TP 5 Homo sapiens (Human)
Please cite: ELM 2016-data update and new functionality of the eukaryotic linear motif resource. (PMID:26615199)

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