|3ky9, resolution 2.73Å ()|
|Gene:||VAV, VAV1 (Homo sapiens)|
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.
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
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[VAV_HUMAN] Couples tyrosine kinase signals with the activation of the Rho/Rac GTPases, thus leading to cell differentiation and/or proliferation.
About this Structure
- Yu B, Martins IR, Li P, Amarasinghe GK, Umetani J, Fernandez-Zapico ME, Billadeau DD, Machius M, Tomchick DR, Rosen MK. Structural and energetic mechanisms of cooperative autoinhibition and activation of Vav1. Cell. 2010 Jan 22;140(2):246-56. PMID:20141838 doi:10.1016/j.cell.2009.12.033
- Li P, Martins IR, Amarasinghe GK, Rosen MK. Internal dynamics control activation and activity of the autoinhibited Vav DH domain. Nat Struct Mol Biol. 2008 Jun;15(6):613-8. Epub 2008 May 18. PMID:18488041 doi:10.1038/nsmb.1428
- Amarasinghe GK, Rosen MK. Acidic region tyrosines provide access points for allosteric activation of the autoinhibited Vav1 Dbl homology domain. Biochemistry. 2005 Nov 22;44(46):15257-68. PMID:16285729 doi:10.1021/bi051126h
- Aghazadeh B, Lowry WE, Huang XY, Rosen MK. Structural basis for relief of autoinhibition of the Dbl homology domain of proto-oncogene Vav by tyrosine phosphorylation. Cell. 2000 Sep 1;102(5):625-33. PMID:11007481