Abstract
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 pathways1–7. SH2 domains possess relatively well conserved residues that form the phosphotyrosine-binding pocket8–11, 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) 5,7,12,13. One such residue, occupying the EF1 position of the +3-binding pocket, is a Thr in the SH2 domain of the Src tyrosine kinase12, but is predicted to be a Trp in the SH2 domain of the Sem-5/drk/Grb2 adaptor protein5. 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.
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Marengere, L., Songyang, Z., Gish, G. et al. SH2 domain specificity and activity modified by a single residue. Nature 369, 502–505 (1994). https://doi.org/10.1038/369502a0
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DOI: https://doi.org/10.1038/369502a0
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