Editors' ChoiceIntramolecular Inhibition

Occlusion of DH Domain Inhibits Vav

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Science's STKE  12 Sep 2000:
Vol. 2000, Issue 49, pp. tw6
DOI: 10.1126/stke.2000.49.tw6

The Dbl homology (DH)-containing protein Vav acts as a guanine nucleotide exchange factor (GEF) for the Rho family of guanine triphosphatases (GTPases), and, in vitro, Vav exhibits specific GEF activity toward Rac protein. Phosphorylation of Vav in response to B cell receptor or T cell receptor stimulation precedes Rac activation. Expression of NH2-terminal deletion (residues 1-182) mutants of Vav leads to chronically activated Vav and increased Rac activity. Phosphorylation of Tyr174 is important for activation of Vav, but until now, the mechanism by which Vav is activated has remained elusive. Aghazadeh et al. have used nuclear magnetic resonance (NMR) to solve the structure of the Vav DH domain in solution. By comparing the structure of the DH domain in the presence or absence of phosphate at Tyr174, the authors identified that, in the inactive state, Tyr174 resides in the Vav DH domain where it occludes Vav's ability to bind and to exchange nucleotides on Rac. Upon phosphorylation of Tyr174, an α helix that contains Tyr174 shifts away from the DH domain, allowing Vav to bind Rac and to exchange GDP for GTP, thus activating Rac. Within the context of the whole protein, it is suggested that the Vav pleckstrin homology (PH) domain lies juxtaposed to the Tyr174-occluded DH domain. Upon lipid binding by the Vav PH domain at the surface of a membrane, the Tyr174 residue becomes available for phosphorylation, leading to Vav activation. Thus, activation of Vav occurs in a multistep process whereby proper membrane localization of Vav leads to its activation.

Aghazadeh, B., Lowry, W.E., Huang, X.-Y., and Rosen, M.K. (2000) Structural basis for relief of autoinhibition of the Dbl homology domain of proto-oncogene Vav by tyrosine phosphorylation. Cell 102: 625-633. [Online Journal]

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