Conditional Peripheral Membrane Proteins: Facing up to Limited Specificity

Regulated relocalization of signaling and trafficking proteins is crucial for the control of many cellular processes and is driven by a series of domains that respond to alterations at membrane surfaces. The first examples of these domains conditional peripheral membrane proteins included Cl, C2, PH, PX, and FYVE domains, which specifically recognize single tightly regulated membrane components such as diacylglycerol or phosphoinositides. The structural basis for this recognition is now well understood, Efforts to identify additional domains with similar functions that bind other targets (or participate in unexplained cellular processes) have not yielded many more examples of specific phospholipid-binding domains. Instead, most of the recently discovered conditional peripheral membrane proteins bind multiple targets 'each with limited specificity), relying on coincidence detection and/or recognizing broader physical properties of the membrane such as charge or curvature. This broader range of recognition modes presents significant methodological challenges for a full structural understanding.