Post-translational modifications of CD36 (SR-B2): Implications for regulation of myocellular fatty acid uptake

Abstract

The membrane-associated protein CD36, now officially designated as SR-B2, is present in various tissues and fulfills multiple cellular functions. In heart and muscle, CD36 is the main (long-chain) fatty acid transporter, regulating myocellular fatty acid uptake via its vesicle-mediated reversible trafficking (recycling) between intracellular membrane compartments and the cell surface. CD36 is subject to various types of post-translational modification. This review focusses on the role of these modifications in further regulation of myocellular fatty acid uptake. Glycosylation, ubiquitination and palmitoylation are involved in regulating CD36 stability, while phosphorylation at extracellular sites affect the rate of fatty acid uptake. In addition, CD36 modification by O-linked N-acetylglucosamine may regulate the translocation of CD36 from endosomes to the cell surface. Acetylation of CD36 has also been reported, but possible effects on CD36 expression and/or functioning have not yet been addressed. Taken together, CD36 is subject to a multitude of post-translational modifications of which their functional implications are beginning to be understood. Moreover, further investigations are needed to disclose whether these post-translational modifications play a role in altered fatty acid uptake rates seen in several pathologies of heart and muscle. This article is part of a special issue entitled: The role of post-translational protein modifications on heart and vascular metabolism edited by Jason R.B. Dyck and Jan F.C. Glatz.

Dynamic role of the transmembrane glycoprotein CD36 (SR-B2) in cellular fatty acid uptake and utilization

“…For instance, besides the already mentioned palmitoylation and O-GlcNAcylation, CD36 also undergoes other post-translational modifications, being phosphorylation, glycosylation and ubiquitination (reviewed in (74)). Phosphorylation (ecto-phosphorylation at positions Thr92 and Ser237 (75)) and ubiquitination likely do not play a role in heart and muscle (74), but may be important in other tissues (76). Glycosylation is a permanent modification and is involved in proper folding of CD36 (77).…”

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

“…The CAT activity showed that G23I in CD36 TM1 corresponding to Gly 25 in SR-BI moderately disrupted the dimerization, whereas Gly 24 in CD36 TM1 corresponding to Gly 26 in SR-BI did not affect the dimerization. Overall, these results revealed that the small residues Gly 12 , Gly 16 , Ala 20 , and Gly 23 is critical to CD36 TM1 homodimerization.…”

“…In this article, we showed that Gly 12 , Gly 16 , Ala 20 , and Gly 23 residues in CD36 are critical to CD36 TM1 homodimerization. The CD36 TM2 domain does contain a conserved polar residue instead of a GXXXG sequence (Fig.…”

“…5). Results of crossing angle distributions, backbone distances, and residue contacts all showed that the Gly 12 , Gly 16 , Ala 20 , and Gly 23 residues in CD36 TM1 were accounted for by the homodimerization (Fig. 6 and supplemental Fig.…”

“…S2). Site-specific mutation scanning of small residues in CD36 TM1 has provided direct evidence of its homodimerization, which was mediated by Gly 12 , Gly 16 , Ala 20 , and Gly 23 residues. By applying CG simulations, we have revealed two distinct packing models (RH1 and RH2) of CD36 TM1 homodimer in a DPPC bilayer (Fig.…”