3KY9

Autoinhibited Vav1

Summary for 3KY9

• Entry DOI: 10.2210/pdb3ky9/pdb
• Descriptor: Proto-oncogene vav, ZINC ION (2 entities in total)
• Functional Keywords: vav1, calponin homology domain, dbl homology domain, pleckstrin homology domain, c1 domain, guanine-nucleotide releasing factor, metal-binding, phosphoprotein, proto-oncogene, sh2 domain, sh3 domain, zinc-finger, apoptosis
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 137668.68

Authors

Tomchick, D.R.,Rosen, M.K.,Machius, M.,Yu, B. (deposition date: 2009-12-04, release date: 2010-02-23, Last modification date: 2024-10-16)

Primary citation

Yu, B.,Martins, I.R.,Li, P.,Amarasinghe, G.K.,Umetani, J.,Fernandez-Zapico, M.E.,Billadeau, D.D.,Machius, M.,Tomchick, D.R.,Rosen, M.K.
Structural and Energetic Mechanisms of Cooperative Autoinhibition and Activation of Vav1
Cell(Cambridge,Mass.), 140:246-256, 2010

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.

PubMed: 20141838
DOI: 10.1016/j.cell.2009.12.033

Experimental method

X-RAY DIFFRACTION (2.731 Å)