PDBsum entry 2foo

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Hydrolase PDB id
Jmol PyMol
Protein chain
137 a.a. *
Waters ×101
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: The crystal structure of the n-terminal domain of hausp/usp7 with p53 peptide 359-362
Structure: Ubiquitin carboxyl-terminal hydrolase 7. Chain: a. Fragment: math domain. Synonym: ubiquitin thiolesterase 7, ubiquitin-specific proc protease 7, deubiquitinating enzyme 7, herpesvirus associat ubiquitin-specific protease. Engineered: yes. P53 peptide. Chain: b.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: hausp, usp7. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes
Biol. unit: Dimer (from PQS)
2.20Å     R-factor:   0.203     R-free:   0.246
Authors: V.Saridakis,Y.Sheng,F.Sarkari,S.Duan,T.Wu,C.H.Arrowsmith,L.F
Key ref:
Y.Sheng et al. (2006). Molecular recognition of p53 and MDM2 by USP7/HAUSP. Nat Struct Mol Biol, 13, 285-291. PubMed id: 16474402 DOI: 10.1038/nsmb1067
13-Jan-06     Release date:   14-Feb-06    
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Protein chain
Pfam   ArchSchema ?
Q93009  (UBP7_HUMAN) -  Ubiquitin carboxyl-terminal hydrolase 7
1102 a.a.
137 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Ubiquitinyl hydrolase 1.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Thiol-dependent hydrolysis of ester, thiolester, 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).


DOI no: 10.1038/nsmb1067 Nat Struct Mol Biol 13:285-291 (2006)
PubMed id: 16474402  
Molecular recognition of p53 and MDM2 by USP7/HAUSP.
Y.Sheng, V.Saridakis, F.Sarkari, S.Duan, T.Wu, C.H.Arrowsmith, L.Frappier.
The ubiquitin-specific protease, USP7, has key roles in the p53 pathway whereby it stabilizes both p53 and MDM2. We show that the N-terminal domain of USP7 binds two closely spaced 4-residue sites in both p53 and MDM2, falling between p53 residues 359-367 and MDM2 residues 147-159. Cocrystal structures with USP7 were determined for both p53 peptides and for one MDM2 peptide. These peptides bind the same surface of USP7 as Epstein-Barr nuclear antigen-1, explaining the competitive nature of the interactions. The structures and mutagenesis data indicate a preference for a P/AXXS motif in peptides that bind USP7. Contacts made by serine are identical and crucial for all peptides, and Trp165 in the peptide-binding pocket of USP7 is also crucial. These results help to elucidate the mechanism of substrate recognition by USP7 and the regulation of the p53 pathway.
  Selected figure(s)  
Figure 1.
Figure 1. Crystal structure of USP7 NTD bound to p53 site 359-PGGS-362. (a) Transparent surface diagrams of p53–USP7. (b) Detailed interactions between USP7 (light gray) and p53 (dark gray). (c) Overlay of p53 (red) and EBNA1 (green) peptides from complex structures. (d) Overlay of p53 (red) and TRANCE-R (yellow) peptides from complex structures, showing conserved interactions with USP7 (purple) and TRAF6 (blue) residues.
Figure 2.
Figure 2. Crystal structure of USP7 NTD bound to p53 site 364-AHSS-367. (a) Transparent surface diagram of USP7 NTD bound by p53 mutant peptide 358-EAGGARAHSS-367 (blue). (b) Detailed interactions between USP7 (light gray) and p53 (dark gray). (c) Overlay of p53 peptides 359-PGGS-362 (red) and 364-AHSS-367 (turquoise) from USP7 complex structures.
Figure 4.
Figure 4. Crystal structure of USP7 NTD bound to MDM2 peptide 4. (a) Transparent surface diagram of MDM2-USP7. (b) Detailed interactions between USP7 (light gray) and MDM2 (dark gray). (c) Overlay of MDM2 (blue) and p53 359-PGGS-362 (red) peptides from USP7 complex structures.
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Mol Biol (2006, 13, 285-291) copyright 2006.  
  Figures were selected by the author.  
    Author's comment    
  The three figures above relate to the three structures 2foo, 2foj and 2fop as follows:
Figure 1: 2foo USP7-p53 359-362 interaction.
Figure 2: 2foj USP7-p53 364-367 interaction.
Figure 4: 2fop USP7-mdm2 interaction.

Literature references that cite this PDB file's key reference

  PubMed id Reference
22056774 H.R.Lee, W.C.Choi, S.Lee, J.Hwang, E.Hwang, K.Guchhait, J.Haas, Z.Toth, Y.H.Jeon, T.K.Oh, M.H.Kim, and J.U.Jung (2011).
Bilateral inhibition of HAUSP deubiquitinase by a viral interferon regulatory factor protein.
  Nat Struct Mol Biol, 18, 1336-1344.
PDB code: 2xxn
21411309 L.Frappier, and C.P.Verrijzer (2011).
Gene expression control by protein deubiquitinases.
  Curr Opin Genet Dev, 21, 207-213.  
21146412 N.E.Davey, G.Travé, and T.J.Gibson (2011).
How viruses hijack cell regulation.
  Trends Biochem Sci, 36, 159-169.  
21258371 Z.Huang, Q.Wu, O.A.Guryanova, L.Cheng, W.Shou, J.N.Rich, and S.Bao (2011).
Deubiquitylase HAUSP stabilizes REST and promotes maintenance of neural progenitor cells.
  Nat Cell Biol, 13, 142-152.  
20885946 F.Sarkari, Y.Sheng, and L.Frappier (2010).
USP7/HAUSP promotes the sequence-specific DNA binding activity of p53.
  PLoS One, 5, e13040.  
20096447 J.Yuan, K.Luo, L.Zhang, J.C.Cheville, and Z.Lou (2010).
USP10 regulates p53 localization and stability by deubiquitinating p53.
  Cell, 140, 384-396.  
19489724 F.E.Reyes-Turcu, K.H.Ventii, and K.D.Wilkinson (2009).
Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes.
  Annu Rev Biochem, 78, 363-397.  
19188362 J.F.Burrows, A.A.Kelvin, C.McFarlane, R.E.Burden, M.J.McGrattan, M.De la Vega, U.Govender, D.J.Quinn, K.Dib, M.Gadina, C.J.Scott, and J.A.Johnston (2009).
USP17 regulates Ras activation and cell proliferation by blocking RCE1 activity.
  J Biol Chem, 284, 9587-9595.  
18952891 S.Daubeuf, D.Singh, Y.Tan, H.Liu, H.J.Federoff, W.J.Bowers, and K.Tolba (2009).
HSV ICP0 recruits USP7 to modulate TLR-mediated innate response.
  Blood, 113, 3264-3275.  
18410249 A.C.Joerger, and A.R.Fersht (2008).
Structural biology of the tumor suppressor p53.
  Annu Rev Biochem, 77, 557-582.  
18784257 G.Chen, H.Huang, O.Fröhlich, Y.Yang, J.D.Klein, S.R.Price, and J.M.Sands (2008).
MDM2 E3 ubiquitin ligase mediates UT-A1 urea transporter ubiquitination and degradation.
  Am J Physiol Renal Physiol, 295, F1528-F1534.  
18410486 J.A.Nathan, S.Sengupta, S.A.Wood, A.Admon, G.Markson, C.Sanderson, and P.J.Lehner (2008).
The ubiquitin E3 ligase MARCH7 is differentially regulated by the deubiquitylating enzymes USP7 and USP9X.
  Traffic, 9, 1130-1145.  
18346885 L.Song, and M.Rape (2008).
Reverse the curse--the role of deubiquitination in cell cycle control.
  Curr Opin Cell Biol, 20, 156-163.  
18833293 N.Sivachandran, F.Sarkari, and L.Frappier (2008).
Epstein-Barr nuclear antigen 1 contributes to nasopharyngeal carcinoma through disruption of PML nuclear bodies.
  PLoS Pathog, 4, e1000170.  
19007433 S.Singhal, M.C.Taylor, and R.T.Baker (2008).
Deubiquitylating enzymes and disease.
  BMC Biochem, 9, S3.  
18260157 Y.Ruano, M.Mollejo, F.I.Camacho, A.Rodríguez de Lope, C.Fiaño, T.Ribalta, P.Martínez, J.L.Hernández-Moneo, and B.Meléndez (2008).
Identification of survival-related genes of the phosphatidylinositol 3'-kinase signaling pathway in glioblastoma multiforme.
  Cancer, 112, 1575-1584.  
17651432 A.Fernández-Montalván, T.Bouwmeester, G.Joberty, R.Mader, M.Mahnke, B.Pierrat, J.M.Schlaeppi, S.Worpenberg, and B.Gerhartz (2007).
Biochemical characterization of USP7 reveals post-translational modification sites and structural requirements for substrate processing and subcellular localization.
  FEBS J, 274, 4256-4270.  
17525743 C.L.Brooks, M.Li, M.Hu, Y.Shi, and W.Gu (2007).
The p53--Mdm2--HAUSP complex is involved in p53 stabilization by HAUSP.
  Oncogene, 26, 7262-7266.  
17499002 F.Toledo, and G.M.Wahl (2007).
MDM2 and MDM4: p53 regulators as targets in anticancer therapy.
  Int J Biochem Cell Biol, 39, 1476-1482.  
17632125 K.Li, B.Ossareh-Nazari, X.Liu, C.Dargemont, and R.Marmorstein (2007).
Molecular basis for bre5 cofactor recognition by the ubp3 deubiquitylating enzyme.
  J Mol Biol, 372, 194-204.
PDB code: 2qiy
17290220 L.F.Stevenson, A.Sparks, N.Allende-Vega, D.P.Xirodimas, D.P.Lane, and M.K.Saville (2007).
The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2.
  EMBO J, 26, 976-986.  
17486072 V.H.Wood, J.D.O'Neil, W.Wei, S.E.Stewart, C.W.Dawson, and L.S.Young (2007).
Epstein-Barr virus-encoded EBNA1 regulates cellular gene transcription and modulates the STAT1 and TGFbeta signaling pathways.
  Oncogene, 26, 4135-4147.  
16905103 M.Renatus, S.G.Parrado, A.D'Arcy, U.Eidhoff, B.Gerhartz, U.Hassiepen, B.Pierrat, R.Riedl, D.Vinzenz, S.Worpenberg, and M.Kroemer (2006).
Structural basis of ubiquitin recognition by the deubiquitinating protease USP2.
  Structure, 14, 1293-1302.
PDB code: 2hd5
16913834 T.Sulea, H.A.Lindner, and R.Ménard (2006).
Structural aspects of recently discovered viral deubiquitinating activities.
  Biol Chem, 387, 853-862.  
16943424 Y.Pereg, S.Lam, A.Teunisse, S.Biton, E.Meulmeester, L.Mittelman, G.Buscemi, K.Okamoto, Y.Taya, Y.Shiloh, and A.G.Jochemsen (2006).
Differential roles of ATM- and Chk2-mediated phosphorylations of Hdmx in response to DNA damage.
  Mol Cell Biol, 26, 6819-6831.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.