4OHD

LEOPARD Syndrome-Associated SHP2/A461T mutant


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.271 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.206 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Molecular basis of gain-of-function LEOPARD syndrome-associated SHP2 mutations.

Yu, Z.H.Zhang, R.Y.Walls, C.D.Chen, L.Zhang, S.Wu, L.Liu, S.Zhang, Z.Y.

(2014) Biochemistry 53: 4136-4151

  • DOI: https://doi.org/10.1021/bi5002695
  • Primary Citation of Related Structures:  
    4OHD, 4OHE, 4OHH, 4OHI, 4OHL

  • PubMed Abstract: 

    The Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP2) is a critical signal transducer downstream of growth factors that promotes the activation of the RAS-ERK1/2 cascade. In its basal state, SHP2 exists in an autoinhibited closed conformation because of an intramolecular interaction between its N-SH2 and protein tyrosine phosphatase (PTP) domains. Binding to pTyr ligands present on growth factor receptors and adaptor proteins with its N-SH2 domain localizes SHP2 to its substrates and frees the active site from allosteric inhibition. Germline mutations in SHP2 are known to cause both Noonan syndrome (NS) and LEOPARD syndrome (LS), two clinically similar autosomal dominant developmental disorders. NS-associated SHP2 mutants display elevated phosphatase activity, while LS-associated SHP2 mutants exhibit reduced catalytic activity. A conundrum in how clinically similar diseases result from mutations to SHP2 that have opposite effects on this enzyme's catalytic functionality exists. Here we report a comprehensive investigation of the kinetic, structural, dynamic, and biochemical signaling properties of the wild type as well as all reported LS-associated SHP2 mutants. The results reveal that LS-causing mutations not only affect SHP2 phosphatase activity but also induce a weakening of the intramolecular interaction between the N-SH2 and PTP domains, leading to mutants that are more readily activated by competing pTyr ligands. Our data also indicate that the residual phosphatase activity associated with the LS SHP2 mutant is required for enhanced ERK1/2 activation. Consequently, catalytically impaired SHP2 mutants could display gain-of-function properties because of their ability to localize to the vicinity of substrates for longer periods of time, thereby affording the opportunity for prolonged substrate turnover and sustained RAS-ERK1/2 activation.


  • Organizational Affiliation

    Department of Biochemistry and Molecular Biology, Indiana University School of Medicine , 635 Barnhill Drive, Indianapolis, Indiana 46202, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein phosphatase non-receptor type 11536Homo sapiensMutation(s): 1 
Gene Names: PTP2CPTPN11SHPTP2
EC: 3.1.3.48
UniProt & NIH Common Fund Data Resources
Find proteins for Q06124 (Homo sapiens)
Explore Q06124 
Go to UniProtKB:  Q06124
PHAROS:  Q06124
GTEx:  ENSG00000179295 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ06124
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.271 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.206 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 54.31α = 90
b = 206.65β = 90
c = 41.881γ = 90
Software Package:
Software NamePurpose
EPICS-baseddata collection
datadata collection
MOLREPphasing
PHENIXrefinement
HKL-3000data reduction
HKL-3000data scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-09-24
    Type: Initial release
  • Version 1.1: 2014-11-05
    Changes: Structure summary
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Refinement description