Intra and Intermolecular Interactions of K-Ras4B: From Structure to Function

Ras proteins are small GTPases that act as signal transducers between cell surface receptors and intracellular signaling cascades. According to the existing paradigm, Ras proteins get activated upon growth factor stimulation of tyrosine kinase receptors which recruit GRB2-SOS complex to the membrane. SOS activates Ras by converting it to Ras-GTP. Ras-GTP binds several downstream effectors that are responsible for activation of multiple cellular processes. Ras proteins consist of four isoforms – H-Ras, N-Ras, K-Ras4A and K-Ras4B. They contain highly homologous catalytic domains, and flexible C-terminal hypervariable regions (HVRs) that differ across Ras isoforms. All the important post-translational modifications occur on the HVR. Since Ras proteins have an almost identical catalytic domain, the HVR is thought to functionally distinguish the Ras isoforms. Ras is mutated in 30% of human tumors. Amongst them, K-Ras4B is frequently mutated in human tumors. In my thesis I investigate how the HVR of K-Ras regulates K-Ras activity through intra and intermolecular interactions, how it establishes specific protein-protein binding, and how it mediates K-Ras dimerization. I focus on identifying unique structural features of K-Ras4B that in the future may be explored for development of isoform specific inhibitors of Ras.