Conformation of an Endogenous Ligand in a Membrane Bilayer for the Macrophage Scavenger Receptor CD36

Abstract

Phagocytic removal of aged or oxidatively damaged cells and macromolecules is an indispensable homeostatic function of the innate immune system. A structurally conserved family of oxidized phospholipids that serve as endogenous high-affinity ligands for the macrophage scavenger receptor CD36 (oxPC_CD36) was recently identified. Enriched within atherosclerotic plaque and senescent cell membranes, oxPC_CD36 promote the uptake of oxidized lipoproteins and cell membranes by macrophages when present at only a few molecules per particle. How macrophages recognize oxPC_CD36 within cellular membranes and lipoprotein surfaces remains unknown. Herein, we deduce the conformation of oxPC_CD36 near the hydrophobic−hydrophilic interface within membrane bilayers by determining multiple critical internuclear distances using nuclear Overhauser enhancement spectroscopy. The molecular model reveals a unique conformation for oxPC_CD36 within bilayers whereby the distal end of the sn-2 acyl chain harboring the structurally conserved CD36 recognition motif protrudes into the aqueous phase. The remarkable conformation elucidated for oxPC_CD36 produces a surface accessible phagocytic “eat me signal” to facilitate senescent cell and oxidized lipoprotein recognition by the scavenger receptor CD36 as part of its immune surveillance function.