Lipid-modified GTPases in the Ras superfamily that mediate a variety of cell signaling processes were thought to be passively anchored to membranes. However, an increasing number of recent studies are finding that membrane binding of these proteins is hardly a passive process, and it involves the soluble catalytic domain as well as the lipid anchor. The catalytic domain adopts multiple orientations on the membrane surface due to internal fluctuations that are modulated by activation status and mutations. Distinct orientation preferences among small GTPases likely lead to differential signaling outcomes, as downstream effectors can sense different orientations. We review recent studies behind this important conclusion.
Keywords: Ras; dynamics; membrane orientation; protein-membrane interaction.