3ky9
From Proteopedia
Autoinhibited Vav1
Structural highlights
FunctionVAV_HUMAN Couples tyrosine kinase signals with the activation of the Rho/Rac GTPases, thus leading to cell differentiation and/or proliferation. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedVav 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. Structural and energetic mechanisms of cooperative autoinhibition and activation of Vav1.,Yu B, Martins IR, Li P, Amarasinghe GK, Umetani J, Fernandez-Zapico ME, Billadeau DD, Machius M, Tomchick DR, Rosen MK Cell. 2010 Jan 22;140(2):246-56. PMID:20141838[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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