Critical residues and motifs for homodimerization of the first transmembrane domain of the plasma membrane glycoprotein CD36

Abstract

The plasma transmembrane (TM) glycoprotein CD36 is critically involved in many essential signaling processes, especially the binding/uptake of long-chain fatty acids and oxidized lowdensity lipoproteins. The association of CD36 potentially activates cytosolic protein tyrosine kinases that are thought to associate with the C-terminal cytoplasmic tail of CD36. To understand the mechanisms by which CD36 mediates ligand binding and signal transduction, we have characterized the homo-oligomeric interaction of CD36 TM domains in membrane environments and with molecular dynamics (MD) simulations. Analysis of pyreneand coumarin-labeled TM1 peptides in SDS by FRET confirmed the homodimerization of the CD36 TM1 peptide. Homodimerization assays of CD36 TM domains with the TOXCAT technique showed that its first TM (TM1) domain, but not the second TM (TM2) domain, could homodimerize in a cell membrane. Smallresidue, site-specific mutation scanning revealed that the CD36 TM1 dimerization is mediated by the conserved small residues Gly CD36 is a transmembrane glycoprotein receptor with many diverse functions, playing a critical role in innate immunity, thrombosis, atherosclerosis, cellular adhesion, and lipid transport (1-5). Widely distributed in a variety of cells, CD36 expression is prominent on platelets and capillary epithelial cells where it is thought to take part in transmembrane signaling and in regulating vessel angiogenesis (6, 7). As a scavenger receptor, CD36 is involved in the binding and uptake of oxidized lowdensity lipoprotein by macrophages and the formation of foam cells during arterial atherogenesis (8 -11). As the receptor for thrombospondin 1 (TSP-1) 3 on endothelial cells, CD36 is reported to mediate the anti-angiogenic effect of TSP-1 (12, 13). CD36 also serves as a selective and non-redundant receptor or sensor of microbial diacylglycerides that signal via the TLR2/6 heterodimer (2).CD36 is the canonical member of class B scavenger receptor family. In this protein family, all the members conform to a two-TM membrane topology, with the first and the second TM domains flanking a large extracellular loop that is highly N-glycosylated (see Fig. 1A). Similar to CD36, many members of the class B scavenger receptor family share a common functional feature in recognizing and binding hydrophobic molecules such as fatty acids and pheromones (14,15). The extracellular domain of CD36 is characterized by a hydrophobic stretch (residues 184 -204) that may interact with the plasma membrane (16). The binding sites of CD36 for fatty acids, modified LDL, the growth hormone releasing peptide, and hexarelin have been mapped to residues 155-183 (17), whereas that for TSP-1 was shown to be residues 93-120 (18). Both intracellular domains of CD36 are relatively short but important for its efficient expression in the plasma membrane (19). Moreover, there are two cysteine residues in each intracellular domain, and their palmitoylation is thought to be an important factor in positioning CD36 into caveolae and lipid rafts (20 -2...

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