The guanine nucleotide exchange factor (GEF) Vav1 plays an important role in T-cell activation and tumorigenesis. In the GEF superfamily, Vav1 has the ability to interact with multiple families of RhoGTPases. The structure of the Vav1-DH-PH-CRD/Rac1 complex to 2.6 Å resolution reveals a unique intramolecular network of contacts between the Vav-1 cysteine rich domain (CRD) and the C-terminal helix of the Vav1 Dbl homology (DH) domain. These unique interactions stabilize the Vav-1 DH domain for its intimate association with the Switch-II region of Rac1 that is critical for the displacement of the guanine nucleotide. Further, a mutational analysis confirms that the atypical CRD is critical for maintaining both optimal guanine nucleotide exchange activity and broader specificity of Vav family GEFs. Taken together, the data outline the detailed nature of Vav1’s ability to contact a range of RhoGTPases using a novel protein-protein interaction network.
Chrencik, J.E., Brooun, A., Zhang, H., Mathews, I.I., Hura, G.L., Foster, S.A., Perry, J.J.P., Streiff, M., Ramage, P., Widmer, H., Bokoch, G.M., Tainer, J., Weckbecker, G. & Kuhn, P., Structural Basis of Guanine Nucleotide ExchangeMediated by the T-cell Essential Vav1, Journal of Molecular Biology (2008), doi:10.1016/j.jmb.2008.05.024