New Aspects of Lipid-Protein Interactions Revealed by Calmodulin Binding to the Lipid Mediator Sphingosylphosphorylcholine

Abstract

Lipid-protein interactions drive core cellular signaling events and regulate the function of most membrane proteins. Despite their significance, molecular details of these interactions are scarcely known. Here we provide mechanistic insight into the binding of the lipid mediator sphingosylphosphorylcholine to calmodulin, the most central and ubiquitous regulator protein in calcium signaling, and present a crystal structure of their complex. Thermodynamic and kinetic analysis of their interaction revealed a peculiar stoichiometry-dependent binding process. At low protein-to-lipid ratios, calmodulin binds with high affinity to lipid micelles. At high protein-to-lipid ratios, however, the resulting complex adopts a compact globular conformation with calmodulin embracing a few lipid molecules, as can be seen in our crystal structure. Intriguingly, the sphingolipid occupies the binding pocket for the amphipatic alpha-helices of calmodulin's target proteins. This finding explains the competitive inhibition of calmodulin function by the signaling lipid, and proposes an utterly novel type of endogenous regulation for the calcium sensor protein. The binding model presented here might be widely applicable to other lipid-protein interactions as well.View Large Image | View Hi-Res Image | Download PowerPoint Slide