Article

Structural and Energetic Mechanisms of Cooperative Autoinhibition and Activation of Vav1

Department of Biochemistry, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8816, USA.
Cell (Impact Factor: 33.12). 01/2010; 140(2):246-56. DOI: 10.1016/j.cell.2009.12.033
Source: PubMed

ABSTRACT Vav proteins are guanine nucleotide exchange factors (GEFs) for Rho family GTPases. They control processes including T cell activation, phagocytosis, and migration of normal and transformed cells. We report the structure and biophysical and cellular analyses of the five-domain autoinhibitory element of Vav1. The catalytic Dbl homology (DH) domain of Vav1 is controlled by two energetically coupled processes. The DH active site is directly, but weakly, inhibited by a helix from the adjacent Acidic domain. This core interaction is strengthened 10-fold by contacts of the calponin homology (CH) domain with the Acidic, pleckstrin homology, and DH domains. This construction enables efficient, stepwise relief of autoinhibition: initial phosphorylation events disrupt the modulatory CH contacts, facilitating phosphorylation of the inhibitory helix and consequent GEF activation. Our findings illustrate how the opposing requirements of strong suppression of activity and rapid kinetics of activation can be achieved in multidomain systems.

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    • "However, this hypothesis is unlikely because we did not detect an increase in Vav2 tyrosine phosphorylation upon Wnt stimulation. Alternatively and more likely, it is possible that the interaction frees the Vav2 catalytic Dbl homology domain from the coordinated auto-inhibition by the Acidic and Calponin homology domains (Yu et al., 2010). Thus, p120-catenin interaction would mimic the effects of Vav2 phosphorylation in the Acidic domain. "
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