Allostery in the Ras-Raf-PI3K-PTEN signaling network at the membrane: Implications for drug discovery

Here, we review the active roles and mechanisms of the plasma membrane and phospholipids in peripheral membrane proteins and lipid-anchored membrane proteins, focusing on the Ras-Raf-PI3K-PTEN signaling network. Data for some phospholipids are scant (or non-existent), whereas for others the mechanistic details are often incomplete-likely due to the challenging nature of membrane dynamics. Identification of the direct, specific interactions of the phospholipids with proteins is often lacking; instead, these lipids are frequently described as creating a negatively charged lipid environment, transiently interacting with proteins. To clarify these elusive yet cardinal mechanisms, we contrast lipid-coupled conformational changes with macroscopic bilayer effects-including altered dimensionality, curvature, and lateral pressure-that collectively modulate protein function by shifting conformational ensembles and local concentration. These lead us to consider specific lipid-binding allostery, membrane-property-mediated conformational coupling, recruitment and orientation effects, and proximity, avidity, and clustering effects. While specific lipid-protein interactions are often transient, both components serve vital active roles in protein function. This is reinforced by distinguishing between canonical, site-specific allosteric regulation and broader membrane-mediated phenomena. Pharmacology at the membrane has been challenging; direct specific lipid-binding allostery is complicated by the often-transient membrane lipid-protein interactions. Coupled with macroscopic bilayer effects, such pharmacology can elicit toxic side-effects. Specifically targeting the regulation of membrane-associated proteins, autoinhibition and activation, may fare better in the clinic. The Ras-Raf-PI3K-PTEN signaling network, which is anchored and controlled by membrane interaction and can be viewed as the heart of cell proliferation, is an especially relevant system to explore.