Crystal structure of human protein tyrosine phosphatase SHP-1 in the open conformation

J Cell Biochem. 2011 Aug;112(8):2062-71. doi: 10.1002/jcb.23125.


SHP-1 belongs to the family of non-receptor protein tyrosine phosphatases (PTPs) and generally acts as a negative regulator in a variety of cellular signaling pathways. Previously, the crystal structures of the tail-truncated SHP-1 and SHP-2 revealed an autoinhibitory conformation. To understand the regulatory mechanism of SHP-1, we have determined the crystal structure of the full-length SHP-1 at 3.1 Å. Although the tail was disordered in current structure, the huge conformational rearrangement of the N-SH2 domain and the incorporation of sulfate ions into the ligand-binding site of each domain indicate that the SHP-1 is in the open conformation. The N-SH2 domain in current structure is shifted away from the active site of the PTP domain to the other side of the C-SH2 domain, resulting in exposure of the active site. Meanwhile, the C-SH2 domain is twisted anticlockwise by about 110°. In addition, a set of new interactions between two SH2 domains and between the N-SH2 and the catalytic domains is identified, which could be responsible for the stabilization of SHP-1 in the open conformation. Based on the structural comparison, a model for the activation of SHP-1 is proposed.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • Enzyme Activation / physiology
  • Enzyme Stability
  • Humans
  • Models, Chemical*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / chemistry*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism
  • Structure-Activity Relationship
  • src Homology Domains


  • PTPN6 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6

Associated data

  • PDB/3PS5