C2 Domains: Versatile Lipid Binding Modules

Abstract

The C2 domain (~130 residues) was originally identified as one of two conserved regulatory domains of Ca2+‐dependent protein kinases C. A large number of proteins containing the C2 domain have been identified since, and most of them are involved in signal transduction or membrane trafficking. Early experiments demonstrated C2 domains could bind bulk phospholipids such as phosphatidylserine or phosphatidylcholine with high affinity and specificity, while more recently; C2 domains have been shown to interact with different phosphoinositides and/or sphingolipids in both Ca2+‐dependent and ‐independent manners. C2 domains have also been shown to bind specific proteins, interact with phosphotyrosine, induce membrane curvature changes, participate in intramolecular interactions, and interact with viral proteins.How the multifaceted C2 domains achieve diverse signaling and interaction properties is only beginning to come to fruition. We have begun a comprehensive and rigorous experimental, computational, single molecule, and structural analysis of the mammalian C2 domain family, which will lead to a better understanding of how these properties manipulate the full‐length proteins' functions.