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 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.
journal_name
Naturejournal_title
Natureauthors
Marengere LE,Songyang Z,Gish GD,Schaller MD,Parsons JT,Stern MJ,Cantley LC,Pawson Tdoi
10.1038/369502a0subject
Has Abstractpub_date
1994-06-09 00:00:00pages
502-5issue
6480eissn
0028-0836issn
1476-4687journal_volume
369pub_type
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