Ras and the Plasma Membrane: A Complicated Relationship

The primary site of Ras signal transduction is the plasma membrane (PM). On the PM, the ubiquitously expressed Ras isoforms, H-, N-, and K-Ras, spatially segregate to nonoverlapping nanometer-sized domains, called nanoclusters, with further lateral segregation into nonoverlapping guanosine triphosphate (GTP)-bound and guanosine diphosphate (GDP)-bound nanoclusters. Effector binding and activation is restricted to GTP nanoclusters, rendering the underlying assembly mechanism essential to Ras signaling. Ras nanoclusters have distinct lipid compositions as a result of lipid-sorting specificity encoded in each Ras carboxy-terminal membrane anchor. The role of the G-domain in regulating anchor-membrane interactions is becoming clearer. Ras G-domains undergo significant conformational orientation changes on guanine nucleotide switch, leading to differential direct contacts between the G-domain and reorganization of the membrane anchor. Ras G-domains also contain weak dimer interfaces, resulting in homodimerization, which is an obligate step of nanoclustering. Modulating the formation of Ras dimers, the lipid composition of the PM or lateral dynamics of key PM phospholipids represent novel mechanisms whereby the extent of Ras nanoclustering can be regulated to tune the gain in Ras signaling circuits.