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PDBsum entry 4dgx

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protein links
Hydrolase PDB id
4dgx
Jmol
Contents
Protein chain
501 a.a.
Waters ×183
PDB id:
4dgx
Name: Hydrolase
Title: Leopard syndrome-associated shp2/y279c mutant
Structure: Tyrosine-protein phosphatase non-receptor type 11 chain: a. Fragment: n-sh2, c-sh2, and ptp domains (unp residues 1-532 synonym: src homology 2 (sh2)-domain containing protein tyr phosphatase-2, shp2, protein-tyrosine phosphatase 1d, ptp-1 protein-tyrosine phosphatase 2c, ptp-2c, sh-ptp2, shp-2, sh engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ptpn11, ptp2c, shptp2. Expressed in: escherichia coli. Expression_system_taxid: 469008.
Resolution:
2.30Å     R-factor:   0.212     R-free:   0.266
Authors: Z.H.Yu,J.Xu,C.D.Walls,L.Chen,S.Zhang,L.Wu,L.N.Wang,S.J.Liu,Z
Key ref: Z.H.Yu et al. (2013). Structural and mechanistic insights into LEOPARD syndrome-associated SHP2 mutations. J Biol Chem, 288, 10472-10482. PubMed id: 23457302 DOI: 10.1074/jbc.M113.450023
Date:
27-Jan-12     Release date:   06-Mar-13    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q06124  (PTN11_HUMAN) -  Tyrosine-protein phosphatase non-receptor type 11
Seq:
Struc:
 
Seq:
Struc:
597 a.a.
501 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.3.1.3.48  - Protein-tyrosine-phosphatase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Protein tyrosine phosphate + H2O = protein tyrosine + phosphate
Protein tyrosine phosphate
+ H(2)O
= protein tyrosine
+ phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     dephosphorylation   2 terms 
  Biochemical function     phosphatase activity     2 terms  

 

 
    reference    
 
 
DOI no: 10.1074/jbc.M113.450023 J Biol Chem 288:10472-10482 (2013)
PubMed id: 23457302  
 
 
Structural and mechanistic insights into LEOPARD syndrome-associated SHP2 mutations.
Z.H.Yu, J.Xu, C.D.Walls, L.Chen, S.Zhang, R.Zhang, L.Wu, L.Wang, S.Liu, Z.Y.Zhang.
 
  ABSTRACT  
 
SHP2 is an allosteric phosphatase essential for growth factor-mediated Ras activation. Germ-line mutations in SHP2 cause clinically similar LEOPARD and Noonan syndromes, two of several autosomal-dominant conditions characterized by gain-of-function mutations in the Ras pathway. Interestingly, Noonan syndrome SHP2 mutants are constitutively active, whereas LEOPARD syndrome SHP2 mutants exhibit reduced phosphatase activity. How do catalytically impaired LEOPARD syndrome mutants engender gain-of-function phenotypes? Our study reveals that LEOPARD syndrome mutations weaken the intramolecular interaction between the N-SH2 and phosphatase domains, leading to a change in SHP2 molecular switching mechanism. Consequently, LEOPARD syndrome SHP2 mutants bind upstream activators preferentially and are hypersensitive to growth factor stimulation. They also stay longer with scaffolding adapters, thus prolonging substrate turnover, which compensates for the reduced phosphatase activity. The study provides a solid framework for understanding how individual SHP2 mutations cause diseases.