The activation and regulation of Rho GTPases are strongly implicated in growth control, tumorigenesis and tumor metastasis. In resting cells Rho GTPases are bound to the Rho-GDP dissociation inhibitor (RhoGDI). It was found recently that the N-terminal domain of ezrin/radixin/moesin (ERM) proteins family binds to RhoGDI, releasing the Rho GTPase that was complexed to it. The interaction of ezrin with RhoGDI, an inhibitor of Rho GTPases will be studied using NMR techniques and mutational analysis. In particular the goal of this study is to understand, at a molecular level, the mechanism of activation of Rho GTPases by ERM proteins. The molecular structure of the N-terminal domain of ezrin will be determined first, then the structure of the ezrin/RhoGDI complex will be solved. Finally mutagenesis, guided by the structure, will be carried out to identify functionally important residues. These experiments will aid in understanding how the formation of this complex leads to the release of the Rho GTPases and their successive activation. Due to the critical role of Rho GTPases in cellular processes, an understanding of the mechanism of their activation by ERM family proteins will contribute to our basic understanding of cell function and to the body of knowledge that can ultimately lead to treatments or cures for cancer.
