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Abstract A09: Cooperative membrane interaction between G-domain and HVR defines unique diffusion behavior of KRAS4b

Rat sarcoma (RAS) family of proteins function as GTP/GDP-dependent control switch to regulate Raf-MAPK effector pathway for cell proliferation and are frequently mutated in human cancer. RAS is anchored to the inner leaflet of the plasma membrane (PM) via C-terminal lipid-tether(s) and hypothesized to concentrate in distinct locations in membrane nano-domains to control the activation step. However, very little is known about the molecular dynamics of RAS on PM and the precise mechanism of activation. Here we characterize the molecular mobility of RAS variants by single-molecule tracking (SMT) method and estimate underlying mobility states. KRAS4b exhibit confined mobility with three diffusive states, a unique characteristic compared to all the other RAS isoforms (KRAS4a, NRAS, and HRAS). Although the major difference across RAS isoforms lies within the C-terminus HVR (hypervariable region) and its post-translational lipid modifications, the additional confinement for KRAS4b is contributed by the G-domain (globular domain) of the protein. Simulation of KRAS4b on membrane revealed a detailed atomistic mechanism that corroborates with the experimental results. Importantly, the oncogenic mutant of KRAS4b shows an altered mode of diffusion, implicating a plausible attribution to/from enhanced effector interaction. This study uncovers a novel underlying principle of KRAS4b functionality on living cell membrane with a potential for innovation in therapeutic strategies against its oncogenic variant. Citation Format: Debanjan Goswami, De Chen, John Columbus, Thomas Turbyville. Cooperative membrane interaction between G-domain and HVR defines unique diffusion behavior of KRAS4b [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr A09.