This talk would deal with the biophysical study of Ras protein-membrane interactions. Ras proteins existing as four isoforms, act as membrane-associated molecular switches in the early steps of signal transduction pathways associated with cell growth and differentiation. For their biological activity, these proteins need to be anchored to membranes, which is achieved by post-translational lipidation. Deregulated isoform-specific Ras signaling accounts for 30% of all human tumors, thus placing them at the focal point of academic and pharmaceutical research. Despite their enormous potential as drug targets, pharmacological intervention of Ras driven cancers has not been realized till date and is dubbed as a “holy grail” in cancer therapy. Due to the common structures of Ras isoforms, most drugs often lead to undesirable off-target effects. Thus, a major hurdle in drugging Ras in a specific manner has been the lack of detailed molecular level characterization of these proteins in their cellular environments. Using various state-of-the-art spectroscopic and microscopic techniques, comprehensive biophysical characterization of the structural and conformational changes in Ras isoforms, upon incorporation into heterogeneous model membrane systems, was accomplished. The main results elucidate key codecs for Ras isoform diversity, providing critical hints to target Ras in an isoform-specific manner. Moreover, highly decisive and critical roles for lipid membranes in Ras protein biophysics, ranging from dictating Ras orientational flexibility, conformational dynamics, and mechanosensitivity, to modulating the interactions of Ras with other proteins would be demonstrated by the presented work.
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