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.