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PDBsum entry 2f1y

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protein links
Hydrolase PDB id
2f1y
Jmol
Contents
Protein chain
136 a.a. *
Waters ×183
* Residue conservation analysis
PDB id:
2f1y
Name: Hydrolase
Title: Crystal structure of the traf-like domain of hausp/usp7 bound to a mdm2 peptide
Structure: Hausp/usp7. Chain: a. Fragment: hausp n-terminal domain with mdm2 peptide fused to its c-terminal. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Resolution:
1.70Å     R-factor:   0.218     R-free:   0.237
Authors: M.Hu,L.Gu,P.D.Jeffrey,Y.Shi
Key ref: M.Hu et al. (2006). Structural basis of competitive recognition of p53 and MDM2 by HAUSP/USP7: implications for the regulation of the p53-MDM2 pathway. PLoS Biol, 4, e27. PubMed id: 16402859
Date:
15-Nov-05     Release date:   07-Feb-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q93009  (UBP7_HUMAN) -  Ubiquitin carboxyl-terminal hydrolase 7
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1102 a.a.
136 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure
* PDB and UniProt seqs differ at 5 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.3.4.19.12  - 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).

 

 
PLoS Biol 4:e27 (2006)
PubMed id: 16402859  
 
 
Structural basis of competitive recognition of p53 and MDM2 by HAUSP/USP7: implications for the regulation of the p53-MDM2 pathway.
M.Hu, L.Gu, M.Li, P.D.Jeffrey, W.Gu, Y.Shi.
 
  ABSTRACT  
 
Herpesvirus-associated ubiquitin-specific protease (HAUSP, also known as USP7), a deubiquitylating enzyme of the ubiquitin-specific processing protease family, specifically deubiquitylates both p53 and MDM2, hence playing an important yet enigmatic role in the p53-MDM2 pathway. Here we demonstrate that both p53 and MDM2 specifically recognize the N-terminal tumor necrosis factor-receptor associated factor (TRAF)-like domain of HAUSP in a mutually exclusive manner. HAUSP preferentially forms a stable HAUSP-MDM2 complex even in the presence of excess p53. The HAUSP-binding elements were mapped to a peptide fragment in the carboxy-terminus of p53 and to a short-peptide region preceding the acidic domain of MDM2. The crystal structures of the HAUSP TRAF-like domain in complex with p53 and MDM2 peptides, determined at 2.3-A and 1.7-A resolutions, respectively, reveal that the MDM2 peptide recognizes the same surface groove in HAUSP as that recognized by p53 but mediates more extensive interactions. Structural comparison led to the identification of a consensus peptide-recognition sequence by HAUSP. These results, together with the structure of a combined substrate-binding-and-deubiquitylation domain of HAUSP, provide important insights into regulation of the p53-MDM2 pathway by HAUSP.
 

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.  
21522127 X.Zhang, F.G.Berger, J.Yang, and X.Lu (2011).
USP4 inhibits p53 through deubiquitinating and stabilizing ARF-BP1.
  EMBO J, 30, 2177-2189.  
20434206 A.Köhler, E.Zimmerman, M.Schneider, E.Hurt, and N.Zheng (2010).
Structural basis for assembly and activation of the heterotetrameric SAGA histone H2B deubiquitinase module.
  Cell, 141, 606-617.
PDB code: 3m99
20404858 C.L.Brooks, and W.Gu (2010).
New insights into p53 activation.
  Cell Res, 20, 614-621.  
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.  
20210752 M.L.Bellows, and C.A.Floudas (2010).
Computational methods for de novo protein design and its applications to the human immunodeficiency virus 1, purine nucleoside phosphorylase, ubiquitin specific protease 7, and histone demethylases.
  Curr Drug Targets, 11, 264-278.  
19946331 N.Kon, Y.Kobayashi, M.Li, C.L.Brooks, T.Ludwig, and W.Gu (2010).
Inactivation of HAUSP in vivo modulates p53 function.
  Oncogene, 29, 1270-1279.  
19834552 F.Sarkari, T.Sanchez-Alcaraz, S.Wang, M.N.Holowaty, Y.Sheng, and L.Frappier (2009).
EBNA1-mediated recruitment of a histone H2B deubiquitylating complex to the Epstein-Barr virus latent origin of DNA replication.
  PLoS Pathog, 5, e1000624.  
19571111 K.D.Wilkinson (2009).
DUBs at a glance.
  J Cell Sci, 122, 2325-2329.  
18410249 A.C.Joerger, and A.R.Fersht (2008).
Structural biology of the tumor suppressor p53.
  Annu Rev Biochem, 77, 557-582.  
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.  
18200608 O.Okhrimenko, and I.Jelesarov (2008).
A survey of the year 2006 literature on applications of isothermal titration calorimetry.
  J Mol Recognit, 21, 1.  
18793145 S.J.Goldenberg, J.L.McDermott, T.R.Butt, M.R.Mattern, and B.Nicholson (2008).
Strategies for the identification of novel inhibitors of deubiquitinating enzymes.
  Biochem Soc Trans, 36, 828-832.  
19007433 S.Singhal, M.C.Taylor, and R.T.Baker (2008).
Deubiquitylating enzymes and disease.
  BMC Biochem, 9, S3.  
17381419 B.Nicholson, J.G.Marblestone, T.R.Butt, and M.R.Mattern (2007).
Deubiquitinating enzymes as novel anticancer targets.
  Future Oncol, 3, 191-199.  
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.  
17380154 K.Becker, N.D.Marchenko, M.Maurice, and U.M.Moll (2007).
Hyperubiquitylation of wild-type p53 contributes to cytoplasmic sequestration in neuroblastoma.
  Cell Death Differ, 14, 1350-1360.  
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.  
18047738 P.Guédat, and F.Colland (2007).
Patented small molecule inhibitors in the ubiquitin proteasome system.
  BMC Biochem, 8, S14.  
17001684 M.C.Barton, S.Akli, and K.Keyomarsi (2006).
Deregulation of cyclin E meets dysfunction in p53: closing the escape hatch on breast cancer.
  J Cell Physiol, 209, 686-694.  
17013413 T.T.Huang, and A.D.D'Andrea (2006).
HAUSP hunting the FOX(O).
  Nat Cell Biol, 8, 1043-1045.  
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.