CD36

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CD36 antigen
Identifiers
Symbol(s)	CD36 SCARB3, GPIV, FAT, GP3B, GP4
Entrez	948
OMIM	173510
RefSeq	NM_001001548
UniProt	P16671
Other data
Locus	Chr. 7 q11.2

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].

Contents 1 Protein Structure and Classification 1.1 Planned additions to this section 2 Genetics, Gene Expression and Regulation 3 Functions of CD36 4 CD36 Deficiency and Alloimmune Thrombocytopenia 5 External links 6 References

[edit] 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 precicts a hydrophobic region near each end of the protein large enough to span cellular membranes. Based on this notion and the oberservation 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]}.

[edit] Planned additions to this section

Protein-protein interactions. Note ^[20] on homooligomerization.

[edit] 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).

[edit] 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.

[edit] 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 deleletion and a combined 839-841 deletion GAG and insertion of AAAAC in Japanese.

[edit] External links

• Scientific American article: "Potential Taste Receptor for Fat Identified"

[edit] References

1. Identification of glycoprotein IV (CD36) as a primary receptor for platelet-collagen adhesion. 1989 May 5; PubMed Free text (PDF - 980K)
2. Sense and antisense cDNA transfection of CD36 (glycoprotein IV) in melanoma cells. Role of CD36 as a thrombospondin receptor. 1992 Aug 15; PubMed Free text (PDF - 1.6M)
3. CD36 directly mediates cytoadherence of Plasmodium falciparum parasitized erythrocytes. 1989 Jul 14; PubMed
4. Oxidized LDL binds to CD36 on human monocyte-derived macrophages and transfected cell lines. Evidence implicating the lipid moiety of the lipoprotein as the binding site. 1995 Feb; PubMed Free text
5. Human CD36 is a high affinity receptor for the native lipoproteins HDL, LDL, and VLDL. 1998 Apr; PubMed Free text
6. Identification of a novel family of oxidized phospholipids that serve as ligands for the macrophage scavenger receptor CD36. 2002 Oct 11; PubMed Free text
7. Reversible binding of long-chain fatty acids to purified FAT, the adipose CD36 homolog. 1996 Sep; PubMed Free text (PDF - 202K)
8. Defective fatty acid uptake modulates insulin responsiveness and metabolic responses to diet in CD36-null mice. 2002 May; PubMed Free text
9. Transgenic expression of CD36 in the spontaneously hypertensive rat is associated with amelioration of metabolic disturbances but has no effect on hypertension. 2003; PubMed Free text (PDF - 146K)
10. Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice. 2000 Apr; PubMed Free text
11. CD36 involvement in orosensory detection of dietary lipids, spontaneous fat preference, and digestive secretions. 2005 Nov; PubMed Free text
12. CD36 deficiency impairs intestinal lipid secretion and clearance of chylomicrons from the blood. 2005 May; PubMed Free text
13. PAS IV, an integral membrane protein of mammary epithelial cells, is related to platelet and endothelial cell CD36 (GP IV). 1990 Jul 31; PubMed
14. A simple method for displaying the hydropathic character of a protein. 1982 May 5; PubMed
15. CD36 is a ditopic glycoprotein with the N-terminal domain implicated in intracellular transport. 2000 Aug 28; PubMed
16. CD36 is palmitoylated on both N- and C-terminal cytoplasmic tails. 1996 Sep 13: PubMed Free text
17. Formation of one or more intrachain disulphide bonds is required for the intracellular processing and transport of CD36. 1997 Dec 1; PubMed Free text
18. Endocytosis of oxidized low density lipoprotein through scavenger receptor CD36 utilizes a lipid raft pathway that does not require caveolin-1. 2003 Nov 14; PubMed Free text
19. FAT/CD36-mediated long-chain fatty acid uptake in adipocytes requires plasma membrane rafts. 2005 Jan; PubMed Free text
20. Thrombospondin induces dimerization of membrane-bound, but not soluble CD36. 1997 Aug; PubMed
21. Gene encoding the collagen type I and thrombospondin receptor CD36 is located on chromosome 7q11.2. 1993 Sep; PubMed
22. A new platelet-specific antigen, Naka, involved in the refractoriness of HLA-matched platelet transfusion. 1989; PubMed
23. A platelet membrane glycoprotein (GP) deficiency in healthy blood donors: Naka- platelets lack detectable GPIV (CD36). 1990 Nov 1; PubMed Free text (PDF - 2.4M)
24. CD36 abnormality and impaired myocardial long-chain fatty acid uptake in patients with hypertrophic cardiomyopathy. 1998 Jul; PubMed Free text (PDF - 300K)