Ras Signaling: Allostery, Conformation, and Function

Abstract

Ras is a small GTPase, controlling signal transduction pathways and promoting cell proliferation and survival. KRAS is frequently mutated in cancer. Ras consists of highly homologous catalytic domains and flexible C-terminal hypervariable regions (HVRs) that differ significantly across Ras isoforms. Ras activation is regulated by guanine nucleotide exchange factors that catalyze the exchange of GDP by GTP, and inactivation is terminated by GTPase-activating proteins that accelerate the intrinsic GTP hydrolysis rate by orders of magnitude. Ras has multiple partners, signals through several key pathways and fulfills critical functions in the cell life. Mutations in Ras are common in a variety of cancers; yet it is still undruggable. Elucidation of Ras conformational ensembles including the ligand-bound conformations, the activated (or inactivated) allosteric modulated states, post-translationally modified states, mutational states, transition states, and nonfunctional states are essential for deciphering Ras functions from its conformational landscapes. Our recent works highlight how these may help in elucidating vital mechanistic questions in Ras biology and hopefully contribute to therapeutic strategies. Funded by Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E.