Abstract
The spatial and temporal regulation of lipid molecules in cell membranes is a hallmark of cellular signaling and membrane trafficking events. Lipid-mediated targeting provides for strict control and versatility, because cell membranes harbor a large number of lipid molecules with variation in head group and acyl chain structures. Signaling and trafficking proteins contain a large number of modular domains that exhibit specific lipid binding properties and play a critical role in their localization and function. Nearly 20 years of research including structural, computational, biochemical and biophysical studies have demonstrated how these lipid-binding domains recognize their target lipid and achieve subcellular localization. The integration of this individual lipid-binding domain data in the context of the full-length proteins, macromolecular signaling complexes, and the lipidome is only beginning to be unraveled and represents a target of therapeutic development. This review brings together recent findings and classical concepts to concisely summarize the lipid-binding domain field while illustrating where the field is headed and how the gaps may be filled in with new technologies.
Highlights
The spatial and temporal regulation of lipid molecules in cell membranes is a hallmark of cellular signaling and membrane trafficking events
The critical role membrane-protein interactions play in the execution and regulation of many cellular processes, including cell signaling and membrane trafficking, has become evident in the past decade
The main gaps in the field lie in understanding the detailed orchestration of cell signaling and membrane trafficking events mediated by lipid-binding domains
Summary
Following its discovery in PKC, the C2 domain (?130 residues) was identified in other proteins such as synaptotagmins and group IVA cytosolic phospholipase A2 (cPLA2a), which bind membranes in a Ca21-dependent fashion. A recent report demonstrated some PH domains anchor to the membrane through aliphatic residues adjacent to the PI-binding site [38]. The Falke laboratory [40] has shed some light on this pathological mechanism, demonstrating that the PI specificity of the AKT1 PH domain is drastically altered by the E17K mutation. Their biophysical analysis demonstrated E17K binds PI[4,5]P2 with even greater affinity than PIP3, and the constitutive PM localization of E17K may be due to binding to pools of PI[4,5]P2 often found in high concentration on the inner leaflet of the PM
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