A Molecular Mechanism for Differential Recognition of Membrane Phosphatidylserine by the Immune Regulatory Receptor Tim4

Abstract

Recognition of phosphatidylserine (PS) lipids exposed on cell surfaces is implicated in both apoptotic cell removal and immune regulation. The PS receptor Tim4 is believed to regulate T cell immunity via phagocystosis of both apoptotic (high PS exposure) and non-apoptotic, activated T cells (intermediate PS exposure). The latter population must be removed at lower efficiency to sensitively control immune tolerance and memory cell population size. Utilizing a combination of interfacial x-ray scattering, membrane binding assays, and molecular dynamics simulations, we demonstrate how Tim4 recognizes PS in the context of the lipid bilayer. Our data reveals that, in addition to the known calcium ion-coordinated, single-PS binding pocket, Tim4 has four weaker sites of potential ionic interactions with PS lipids. This organization makes Tim4 sensitive to PS surface concentration in a manner capable of supporting differential membrane recognition on the basis of PS exposure level. Tim1 is distinctly less sensitive, likely reflecting the differences in immunological function of Tim1.