CD36

CD36 is an integral membrane protein found on the surface of many cell types in vertebrate animals and is also known as FAT, SCARB3, GP88, glycoprotein IV (gpIV) and glycoprotein IIIb (gpIIIb). CD36 is a member of the class B scavenger receptor family of cell surface proteins. CD36 binds many ligands including collagen [1], thrombospondin [2], erythrocytes parasitized with Plasmodium falciparum [3], oxidized low density lipoprotein [4], native lipoproteins [5], oxidized phospholipids [6] and long-chain fatty acids [7]. Recent work using genetically modified rodents have identified a clear role for CD36 in fatty acid and glucose metabolism [8], [9], heart disease [10], taste [11] and dietary fat processing in the intestine [12]. It may be involved in glucose intolerance, atherosclerosis, arterial hypertension, diabetes, cardiomyopathy and Alzheimer's disease.

Protein Structure and Classification


In humans, rats and mice, CD36 consists of 472 amino acids with a predicted molecular weight of approximately 53,000 Da. However, CD36 is extensively glycosylated and has an apparent molecular weight of 88,000 Da as determined by SDS polyacrylamide gel electrophoresis [13].

Using Kyte-Doolittle analysis [14], the amino acid sequence of CD36 precincts a hydrophobic region near each end of the protein large enough to span cellular membranes. Based on this notion and the observation that CD36 is found on the surface of cells, CD36 is thought to have a 'hairpin-like' structure with α-helices at the C- and N- termini projecting through the membrane and a larger extracellular loop (Fig. 1). This topology is supported by transfection experiments in cultured cells using deletion mutants of CD36 [15], [16]. Unlike the topology and proposed structure of transmembrane α-helices, very little is known about the secondary structure of the extracellular loop.

Besides glycosylation, additional posttranslational modifications have been reported for CD36. Disulfide linkages between 4 of the 6 cysteine residues in the extracellular loop are required for efficient intracellular processing and transport of CD36 to the plasma membrane [17]. It is not clear what role these linkages play on the function of the mature CD36 protein on the cell surface. CD36 is also posttranslationally modified with 4 palmitoyl chains, 2 on each of the two intracellular domains [16]. The function of these lipid modifications is currently unknown but they likely promote the association of CD36 with the membrane and possibly lipid rafts which appear to be important for some CD36 functions [18], [19].

Planned additions to this section
Protein-protein interactions. Note [20] on homooligomerization.

Genetics, Gene Expression and Regulation
CD36 is found on platelets, erythrocytes, monocytes, differentiated adipocytes, mammary epithelial cells, spleen cells and some skin microdermal endothelial cells.

The gene is located on the long arm of chromosome 7 at band 11.2 (7q11.2 [21]) and is encoded by 15 exons that extend over more than 32 kilobases. Both the 5' and the 3' untranslated regions contain introns: the 5' with two and the 3' one. The predicted cytoplasmic and transmembrane regions, found at the terminal ends of the polypeptide chain are encoded by single exons and the extracellular domain is encoded by 11 exons. Alternative splicing of the untranslated regions gives rise to at least two mRNA species.

The transcription initiation site of the CD36 gene has been mapped to 289 nucleotides upstream from the translational start codon and a TATA box and several putative cis regulatory regions lie further 5'. A binding site for PEBP2/CBF factors has been identified between -158 and -90 and disruption of this site reduces expression. The gene is the transcriptional control of the nuclear receptor PPAR -RXR (peroxisome proliferator-activated receptor - retinoic-X-receptor) and gene expression can be up regulated using synthetic and natural ligands for PPAR -RXR, including the thiazoledinedione class of anti-diabetic drugs and the vitamin A metabolite 9-cis-retinoic acid.

Infections with the human malaria parasite Plasmodium falciparum are characterized by sequestration of erythrocytes infected with mature forms of the parasite and CD36 has been shown to be a major sequestration receptor on microvascular endothelial cells. Parasitised erythrocytes become adherent to endothelium at the trophozoite/schizonts stage simultaneous with the appearance of the var gene product (erythrocyte membrane protein 1) on the erythrocyte surface. The appearance of erythrocyte membrame protein 1 (PfEMP1) on the erythrocyte surface is a temperature dependent phenomenon which is due to increased protein trafficking to the erythrocyte surface at the raised temperature. PfEMP1 can bind other endothelial receptors - thrombospondin (TSP) and intercellular adhesion molecule 1 (ICAM-1) – in addition to CD36 - and genes other than PfEMP1 also bind to CD36: cytoadherence linked protein (clag) and sequestrin. The PfEMP1 binding site on CD36 is known to be located on exon 5.

CD36 on the surface of the platelets has been shown to be involved in adherence but direct adherence to the endothelium by the infected erythrocytes also occurs. Autoaggregation of infected erythrocytes by platelets has been shown to correlate with severe malaria and cerebral malaria in particular and antiplatelet antibodies may offer some protection.

Several lines of evidence suggest that mutations in CD36 are protective against malaria: mutations in the promoters and within introns and in exon 5 reduce the risk of severe malaria. Gene diversity studies suggest there has been positive selection on this gene presumably due to malarial selection pressure. Dissenting reports are also known suggesting that CD36 is not the sole determinant of severe malaria. In addition a role for CD36 has been found in the clearance of gametocytes (stages I and II).

CD36 has been shown to have a role in the innate immune response to malaria in mouse models. . Compared with wild type mice CD36(-/-) mice the cytokine induction response and parasite clearance were impaired. Earlier peak parasitemias, higher parasite densities and higher mortality were noted. It is thought that CD36 is involved in the Plasmodium falciparum glycophosphatidylinositol (PfGPI) induced MAPK activation and proinflammatory cytokine secretion. When macrophages were exposed to PfGPI the proteins ERK1/2, JNK, p38, and c-Jun became phosphorylated. All these proteins are involved as secondary messengers in the immune response. These responses were blunted in the CD36(-/-) mice. Also in the CD36(-/-) macrophages secreted significantly less TNF-alpha on exposure to PfGPI. Work is on going to determine how these exactly how these responses provide protection against malaria.

Functions of CD36
The protein itself belongs to the class B scavenger receptor family which includes receptor for selective cholesteryl ester uptake, scavenger receptor class B type I (SR-BI), and lysosomal integral membrane protein II (LIMP-II). CD36 interacts with a number of ligands, including collagen types I and IV, thrombospondin, erythrocytes parasitized with Plasmodium falciparum, platelet-agglutinating protein p37, oxidized low density lipoprotein and long-chain fatty acids. On macrophages CD36 forms part of a non opsonic receptor (the scavenger receptor CD36/alphaV beta3 complex) and is involved in phagocytosis. CD36 has also been implicated in hemostasis, thrombosis, malaria, inflammation, lipid metabolism and atherogenesis.

CD36 Deficiency and Alloimmune Thrombocytopenia
Mutations in the human CD36 gene were first identified in a patient who, despite multiple platelet transfusions, continued to exhibit low platelet levels [22], [23]. This condition is known as refractoriness to platelet transfusion. Subsequent studies have shown that CD36 found on the surface of platelets.

myocardial FA uptake in humans [24]

CD36 is also known as glycoprotein IV (gpIV) or glycoprotein IIIb (gpIIIb) in platelets and gives rise to the Naka antigen. The Naka null phenotype is found in 0.3% of Caucasians and appears to be asymptomatic. Depending on the nature of the mutation in codon 90 CD36 may be absent either on both platelets and monocytes (type 1) or platelets alone (type 2). The null phenotype is more common in African (2.5%), Japanese, and other Asian populations (5-11%). The molecular basis is known for some cases: T1264G in both Kenyans and Gambians; C478T (50%), 539 deletion of AC and 1159 insertion of an A, 1438-1449 deletion and a combined 839-841 deletion GAG and insertion of AAAAC in Japanese.

Additional references
Febbraio M, Silverstein RL. (2007) CD36: Implications in cardiovascular disease. Int. J. Biochem. Cell. Biol.