Crystal Structure of the Tyrosine Phosphatase SHP-2

Cell. 1998 Feb 20;92(4):441-50. doi: 10.1016/s0092-8674(00)80938-1.

Abstract

The structure of the SHP-2 tyrosine phosphatase, determined at 2.0 angstroms resolution, shows how its catalytic activity is regulated by its two SH2 domains. In the absence of a tyrosine-phosphorylated binding partner, the N-terminal SH2 domain binds the phosphatase domain and directly blocks its active site. This interaction alters the structure of the N-SH2 domain, disrupting its phosphopeptide-binding cleft. Conversely, interaction of the N-SH2 domain with phosphopeptide disrupts its phosphatase recognition surface. Thus, the N-SH2 domain is a conformational switch; it either binds and inhibits the phosphatase, or it binds phosphoproteins and activates the enzyme. Recognition of bisphosphorylated ligands by the tandem SH2 domains is an integral element of this switch; the C-terminal SH2 domain contributes binding energy and specificity, but it does not have a direct role in activation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Crystallography
  • Enzyme Activation
  • Escherichia coli / genetics
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Molecular Sequence Data
  • Phosphoproteins / metabolism
  • Protein Conformation
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases / chemistry*
  • Protein Tyrosine Phosphatases / metabolism*
  • SH2 Domain-Containing Protein Tyrosine Phosphatases
  • Sequence Homology, Amino Acid
  • Substrate Specificity
  • src Homology Domains / physiology

Substances

  • Intracellular Signaling Peptides and Proteins
  • Phosphoproteins
  • PTPN11 protein, human
  • PTPN6 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases
  • SH2 Domain-Containing Protein Tyrosine Phosphatases