Dynamic Coupling Between the SH2 and SH3 Domains of C-Src and Hck Underlies Their Inactivation by C-Terminal Tyrosine Phosphorylation

Matthew A. Young, Stefania Gonfloni, Giulio Superti-Furga, Benoit Roux and John Kuriyan

Cell. Young et al. 105:115.

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Summary

The effect of C-terminal tyrosine phosphorylation on molecular motions in the Src kinases Hck and c-Src is investigated by molecular dynamics simulations. The SH2 and SH3 domains of the inactive kinases are seen to be tightly coupled by the connector between them, impeding activation. Dephosphorylation of the tail reduces the coupling between the SH2 and SH3 domains in the simulations, as does replacement of connector residues with glycine. A mutational analysis of c-Src expressed in Schizosaccharomyces pombe demonstrates that replacement of residues in the SH2-SH3 connector with glycine activates c-Src. The SH2-SH3 connector appears to be an inducible "snap-lock" that clamps the SH2 and SH3 domains upon tail phosphorylation, but which allows flexibility when the tail is released.

Figures (click on the small image to view a high resolution one)

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Other images

Other images and data

AMBER format topology data for Phospho-Tyrosine residue (-2 charge state)

Animations

Note: Solvent (water and ions) have been removed from the animations for clarity.
 

        3ns MD of lck SH2 domain complexed to YEEI

        5ns MD of the closed form of Hck

        5ns MD of the closed form of Src

        5ns MD of the SH3-SH2 connector Glycine mutant

        Targetted MD (150ps) modeling the closed to open transition of  Hck

        Model of the closed to open transition of the kinase domain of Src.

        15.5ns MD of an SH3-SH2 construct from Hck, avi format