All RAS isoforms contain a C-terminal cysteine residue that is farnesylated and carboxymethylated. These 22 to 23 amino acids mediate interactions with the lipid bilayer and contain key residues that are post-translationally modified ( Ahearn et al., 2012). RAS proteins associate with the plasma membrane (PM) through the HVR. The protein’s lateral mobility, nanoclustering of both RAS and lipid species, and interactions between specific lipid species and amino acid residues in the C-terminal hypervariable region (HVR) are all necessary for its function however, precisely how this is regulated, and in what order events occur has not been fully characterized ( Murakoshi et al., 2004)(( Lommerse et al., 2005 Nan et al., 2015 Zhou et al., 2017). RAS biology is characterized by its dynamic association with the plasma membrane.

In this active state, RAS is in a conformation that favors interaction with several effectors, including RAF, a serine/threonine kinase that, when complexed with RAS at the membrane, phosphorylates its substrate MEK and initiates the mitogenic-activated protein kinase signaling cascade ( Moodie et al., 1993 Van Aelst et al., 1993 Warne et al., 1993). In oncogenic mutants, this molecular switch mechanism is damaged, and RAS becomes constitutively active-or locked in a GTP-loaded state. RAS is an oncoprotein that functions as a molecular switch at the apex of a signaling network ( Stephen et al., 2014) regulating cell differentiation and sustaining cell proliferation, survival, and migration. To understand the altered mobility of an oncogenic KRAS4b, we used complementary experimental and molecular dynamics simulation approaches to reveal a detailed mechanism. KRAS4b exhibits confined mobility with three diffusive states distinct from the other RAS isoforms (KRAS4a, NRAS, and HRAS) and although most of the amino acid differences between RAS isoforms lie within the hypervariable region, the additional confinement of KRAS4b is largely determined by the protein’s globular domain. Here, we characterize RAS in live human and mouse cells using single-molecule-tracking methods and estimate RAS mobility parameters.

However, little is known about RAS membrane dynamics and the details of RAS activation of downstream signaling. RAS proteins concentrate in the plasma membrane via lipid-tethers and hypervariable region side-chain interactions in distinct nano-domains. The RAS proteins are GTP-dependent switches that regulate signaling pathways and are frequently mutated in cancer.

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