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|Title: ||SH2 domain specificity and activity modified by a single residue|
|Authors: ||Marengere, Luc E. M.|
Gish, Gerald D.
Schaller, Michael D.
Parsons, J. Thomas
Stern, Michael J.
Cantley, Lewis C.
|Keywords: ||Adaptor Proteins, Signal Transducing|
Caenorhabditis elegans Proteins
Focal Adhesion Protein-Tyrosine Kinases
GRB2 Adaptor Protein
|Issue Date: ||1994|
|Publisher: ||Nature Publishing Group|
|Citation: ||Nature. 1994 Jun 9;369(6480):502-5.|
|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 phosphotyrosinebinding
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 kinase 12, 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
|Appears in Collections:||Pawson, Tony|
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