RAS G-domains allosterically contribute to the recognition of lipid headgroups and acyl chains

Membrane anchors of RAS play major roles in select lipid enrichment of RAS on the plasma membrane. Arora et al. show that the cytoplasmic RAS G-domains fine-tune selectivity of lipids. Their findings provide a mechanism for the allele-specific oncogenesis of KRAS4B. Mutant RAS are major contributors to cancer and signal primarily from nanoclusters on the plasma membrane (PM). Their C-terminal membrane anchors are main features of membrane association. However, the same RAS isoform bound to different guanine nucleotides spatially segregate. Different RAS nanoclusters all enrich a phospholipid, phosphatidylserine (PS). These findings suggest more complex membrane interactions. Our electron microscopy-spatial analysis shows that wild-types, G12V mutants, and membrane anchors of isoforms HRAS, KRAS4A, and KRAS4B prefer distinct PS species. Mechanistically, reorientation of KRAS4B G-domain exposes distinct residues, such as Arg 135 in orientation state 1 (OS1) and Arg 73/Arg 102 in OS2, to the PM and differentially facilitates the recognition of PS acyl chains. Allele-specific oncogenic mutations of KRAS4B also shift G-domain reorientation equilibrium. Indeed, KRAS4BG12V, KRAS4BG12D, KRAS4BG12C, KRAS4BG13D, and KRAS4BQ61H associate with PM lipids with headgroup and acyl chain specificities. Distribution of these KRAS4B oncogenic mutants favors different nanoscale membrane topography. Thus, RAS G-domains allosterically facilitate membrane lateral distribution.