SH2 domain specificity and activity modified by a single residue

Nature. 1994 Jun 9;369(6480):502-5. doi: 10.1038/369502a0.


Many intracellular targets of protein-tyrosine kinases possess Src homology 2 (SH2) domains that directly recognize phosphotyrosine-containing sites on autophosphorylated growth factor receptors and cytoplasmic proteins, and thereby mediate the activation of biochemical signalling pathways. SH2 domains possess relatively well conserved residues that form the phosphotyrosine-binding pocket, and more variable residues that are implicated in determining binding specificity by recognition of the three amino acids carboxy-terminal to phosphotyrosine (the +1 to +3 positions). One such residue, occupying the EF1 position of the +3-binding pocket, is a Thr in the SH2 domain of the Src tyrosine kinase, but is predicted to be a Trp in the SH2 domain of the Sem-5/drk/Grb2 adaptor protein. Here we report that changing this residue in the Src SH2 domain from Thr to Trp switches its selectivity to resemble that of the Sem-5/drk/Grb2 SH2 domain. Furthermore, this mutant Src SH2 domain effectively substitutes for the SH2 domain of the Sem-5 protein in activation of the Ras pathway in vivo. These results identify a residue that can modify SH2 selectivity, and indicate that the biological activity of an SH2 domain correlates with its binding specificity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins*
  • Cell Adhesion Molecules / metabolism
  • Drosophila
  • Drosophila Proteins*
  • Focal Adhesion Protein-Tyrosine Kinases
  • GRB2 Adaptor Protein
  • Helminth Proteins / chemistry
  • Helminth Proteins / metabolism
  • Insect Hormones / chemistry
  • Insect Hormones / metabolism
  • Molecular Sequence Data
  • Protein Binding
  • Protein-Tyrosine Kinases / metabolism*
  • Proteins / chemistry
  • Proteins / metabolism
  • Proto-Oncogene Proteins pp60(c-src) / metabolism*
  • Threonine / metabolism*
  • Tryptophan / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Caenorhabditis elegans Proteins
  • Cell Adhesion Molecules
  • Drosophila Proteins
  • GRB2 Adaptor Protein
  • Helminth Proteins
  • Insect Hormones
  • Proteins
  • Sem-5 protein, C elegans
  • drk protein, Drosophila
  • Threonine
  • Tryptophan
  • Protein-Tyrosine Kinases
  • Focal Adhesion Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins pp60(c-src)