Structural and Energetic Mechanisms of Cooperative Autoinhibition and Activation of Vav1

Bingke Yu, Ilídio R.S. Martins, Pilong Li, Gaya K. Amarasinghe, Junko Umetani, Martin E. Fernandez-Zapico, Daniel D. Billadeau, Mischa Machius, Diana R. Tomchick, Michael K. Rosen

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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.

Original languageEnglish
Pages (from-to)246-256
Number of pages11
JournalCell
Volume140
Issue number2
DOIs
StatePublished - Jan 22 2010
Externally publishedYes

Keywords

  • SIGNALING

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    Yu, B., Martins, I. R. S., Li, P., Amarasinghe, G. K., Umetani, J., Fernandez-Zapico, M. E., Billadeau, D. D., Machius, M., Tomchick, D. R., & Rosen, M. K. (2010). Structural and Energetic Mechanisms of Cooperative Autoinhibition and Activation of Vav1. Cell, 140(2), 246-256. https://doi.org/10.1016/j.cell.2009.12.033