Differential Phosphatidylserine Recognition by the Tim Family of Immune Regulatory Receptors

Abstract

Recognition of phosphatidylserine (PS) lipids exposed on the extracellular leaflet of plasma membranes is implicated in both apoptotic cell removal and immune regulation. Using a combination of interfacial x-ray scattering, molecular dynamics simulations, and membrane binding assays, we examined how different members of the T-cell immunoglobulin and mucin-domain-containing (Tim) family of PS receptors recognize PS in the context of a lipid bilayer. Our findings demonstrate that in addition to the known Ca2+-coordinated, single-PS binding pocket, the different Tim proteins have different number of weaker sites of potential ionic interactions with PS lipids, and show different levels of hydrophobic insertion. These subtle differences in PS recognition likely contribute to the differences in immunological function among the Tim proteins.