|CD36 molecule (thrombospondin receptor)|
Predicted topology of CD36 in the plasma membrane
|External IDs||ChEMBL: GeneCards:|
|RNA expression pattern|
CD36 (Cluster of Differentiation 36) 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, thrombospondin, erythrocytes parasitized with Plasmodium falciparum, oxidized low density lipoprotein, native lipoproteins, oxidized phospholipids, and long-chain fatty acids.
Recent work using genetically modified rodents have identified a clear role for CD36 in fatty acid and glucose metabolism, heart disease, taste, and dietary fat processing in the intestine. It may be involved in glucose intolerance, atherosclerosis, arterial hypertension, diabetes, cardiomyopathy and Alzheimer's disease.
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.
Using Kyte-Doolittle analysis, the amino acid sequence of CD36 predicts 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.
Unlike the topology and proposed structure of transmembrane α-helices, very little is known about the secondary structure of the extracellular loop. 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. It is not clear what role these linkages play on the function of the mature CD36 protein on the cell surface.
Posttranslational modification 
Besides glycosylation, additional posttranslational modifications have been reported for CD36. CD36 is modified with 4 palmitoyl chains, 2 on each of the two intracellular domains. 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.
Protein-protein interactions 
In the absence of ligand, membrane bound CD36 exists primarily in a monomeric state. However exposure to the thrombospondin ligand causes CD36 to dimerize. This dimerization has been proposed to play an important role in CD36 signal transduction.
The gene is located on the long arm of chromosome 7 at band 11.2 (7q11.2) 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. Exons 1, 2 and first 89 nucleotides of exon 3 and as well as exon 15 are non-coding. Exon 3 contains encodes the N-terminal cytoplasmic and transmembrane domains. The C-terminal cytoplasmic and transmembrane regions is encoded by exon 14. The extracellular domain is encoded by the central 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 heterodimer (Peroxisome proliferator-activated receptor – Retinoid X receptor) and gene expression can be up regulated using synthetic and natural ligands for PPAR and RXR, including the thiazolidinedione class of anti-diabetic drugs and the vitamin A metabolite 9-cis-retinoic acid respectively.
Tissue distribution 
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.
On binding a ligand the protein and ligand are internalized. This internalization is independent of macropinocytosis and occurs by an actin dependent mechanism requiring the activation Src-family kinases, JNK and Rho-family GTPases. Unlike macropinocytosis this process is not affected by inhibitors of phosphatidylinositol 3-kinase or Na+/H+ exchange.
Recently, CD36 was linked to store-operated calcium flux, phospholipase A2 activation, and production of prostaglandin E2
Clinical significance 
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 adhere 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 membrane 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 ongoing to determine how these exactly how these responses provide protection against malaria.
CD36 deficiency and alloimmune thrombocytopenia 
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. The null phenotype is more common in African (2.5%), Japanese, and other Asian populations (5-11%).
Mutations in the human CD36 gene were first identified in a patient who, despite multiple platelet transfusions, continued to exhibit low platelet levels. This condition is known as refractoriness to platelet transfusion. Subsequent studies have shown that CD36 found on the surface of platelets. This antigen is recognized by the monoclonal antibodies (MAbs) OKM5 and OKM8. It is bound by the Plasmodium falciparum protein sequestrin.
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). Type 2 has been divided into two subtypes - a and b. Deficiency restricted to the platelets alone is known as type 2a; if CD36 is also absent from the erythoblasts the phenotype is classified as type 2b. 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.
In a study of 827 apparently healthy Japanese volunteers, type I and II deficiencies were found in 8 (1.0%) and 48 (5.8%) respectively. In 1127 healthy French blood donors (almost all of whom were white Europeans) no CD36 deficiency was found. In a second group only 1 of 301 white test subjects was found to be CD36 deficient. 16 of the 206 sub-Saharan black Africans and 1 of 148 black Caribbeans were found to be CD36 -ve. Three of 13 CD36 -ve persons examined had anti CD36 antibodies. In a group of 250 black American blood donors 6 (2.4%) were found to be Naka antigen negative.
Blood pressure 
This gene has also been implicated in the control of blood pressure.
Fatty acid uptake 
Related proteins 
See also 
- Tandon NN, Kralisz U, Jamieson GA (5 May 1989). "Identification of glycoprotein IV (CD36) as a primary receptor for platelet-collagen adhesion". J. Biol. Chem. 264 (13): 7576–83. PMID 2468670.
- Silverstein RL, Baird M, Lo SK, Yesner LM (15 August 1992). "Sense and antisense cDNA transfection of CD36 (glycoprotein IV) in melanoma cells. Role of CD36 as a thrombospondin receptor". J. Biol. Chem. 267 (23): 16607–12. PMID 1379600.
- Oquendo P, Hundt E, Lawler J, Seed B (July 1989). "CD36 directly mediates cytoadherence of Plasmodium falciparum parasitized erythrocytes". Cell 58 (1): 95–101. doi:10.1016/0092-8674(89)90406-6. PMID 2473841.
- 16. Endemann G, Stanton LW, Madden KS, Bryant CM, White RT, Protter A (5 June 1993). "CD36 is a receptor for oxidized-low-density lipoprotein". J. Biol. Chem. 268 (16): 11811–16. PMID 7685021.
- Nicholson AC, Frieda S, Pearce A, Silverstein RL (1 February 1995). "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". Arterioscler. Thromb. Vasc. Biol. 15 (2): 269–75. doi:10.1161/01.ATV.15.2.269. PMID 7538425.
- Calvo D, Gómez-Coronado D, Suárez Y, Lasunción MA, Vega MA (1 April 1998). "Human CD36 is a high affinity receptor for the native lipoproteins HDL, LDL, and VLDL". J. Lipid Res. 39 (4): 777–88. PMID 9555943.
- Podrez EA, Poliakov E, Shen Z, Zhang R, Deng Y, Sun M, Finton PJ, Shan L, Gugiu B, Fox PL, Hoff HF, Salomon RG, Hazen SL (October 2002). "Identification of a novel family of oxidized phospholipids that serve as ligands for the macrophage scavenger receptor CD36". J. Biol. Chem. 277 (41): 38503–16. doi:10.1074/jbc.M203318200. PMID 12105195.
- Baillie AG, Coburn CT, Abumrad NA (September 1996). "Reversible binding of long-chain fatty acids to purified FAT, the adipose CD36 homolog". J. Membr. Biol. 153 (1): 75–81. doi:10.1007/s002329900111. PMID 8694909.
- Hajri T, Han XX, Bonen A, Abumrad NA (May 2002). "Defective fatty acid uptake modulates insulin responsiveness and metabolic responses to diet in CD36-null mice". J. Clin. Invest. 109 (10): 1381–9. doi:10.1172/JCI14596. PMC 150975. PMID 12021254.
- Pravenec M, Landa V, Zídek V, Musilová A, Kazdová L, Qi N, Wang J, St Lezin E, Kurtz TW (2003). "Transgenic expression of CD36 in the spontaneously hypertensive rat is associated with amelioration of metabolic disturbances but has no effect on hypertension" (PDF). Physiol Res 52 (6): 681–8. PMID 14640889.
- Febbraio M, Podrez EA, Smith JD, Hajjar DP, Hazen SL, Hoff HF, Sharma K, Silverstein RL (April 2000). "Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice". J. Clin. Invest. 105 (8): 1049–56. doi:10.1172/JCI9259. PMC 300837. PMID 10772649.
- Laugerette F, Passilly-Degrace P, Patris B, Niot I, Febbraio M, Montmayeur JP, Besnard P (November 2005). "CD36 involvement in orosensory detection of dietary lipids, spontaneous fat preference, and digestive secretions". J. Clin. Invest. 115 (11): 3177–84. doi:10.1172/JCI25299. PMC 1265871. PMID 16276419.
- Drover VA, Ajmal M, Nassir F, Davidson NO, Nauli AM, Sahoo D, Tso P, Abumrad NA (May 2005). "CD36 deficiency impairs intestinal lipid secretion and clearance of chylomicrons from the blood". J. Clin. Invest. 115 (5): 1290–7. doi:10.1172/JCI21514. PMC 1074677. PMID 15841205.
- Rać ME, Safranow K, Poncyljusz W (2007). "Molecular basis of human CD36 gene mutations". Mol. Med. 13 (5-6): 288–96. doi:10.2119/2006-00088.Rac. PMC 1936231. PMID 17673938.
- Greenwalt DE, Watt KW, So OY, Jiwani N (July 1990). "PAS IV, an integral membrane protein of mammary epithelial cells, is related to platelet and endothelial cell CD36 (GP IV)". Biochemistry 29 (30): 7054–9. doi:10.1021/bi00482a015. PMID 1699598.
- Kyte J, Doolittle RF (May 1982). "A simple method for displaying the hydropathic character of a protein". J. Mol. Biol. 157 (1): 105–32. doi:10.1016/0022-2836(82)90515-0. PMID 7108955.
- Gruarin P, Thorne RF, Dorahy DJ, Burns GF, Sitia R, Alessio M (August 2000). "CD36 is a ditopic glycoprotein with the N-terminal domain implicated in intracellular transport". Biochem. Biophys. Res. Commun. 275 (2): 446–54. doi:10.1006/bbrc.2000.3333. PMID 10964685.
- Tao N, Wagner SJ, Lublin DM (September 1996). "CD36 is palmitoylated on both N- and C-terminal cytoplasmic tails". J. Biol. Chem. 271 (37): 22315–20. doi:10.1074/jbc.271.37.22315. PMID 8798390.
- Gruarin P, Sitia R, Alessio M (December 1997). "Formation of one or more intrachain disulphide bonds is required for the intracellular processing and transport of CD36". Biochem. J. 328 (2): 635–42. PMC 1218965. PMID 9371725.
- Zeng Y, Tao N, Chung KN, Heuser JE, Lublin DM (November 2003). "Endocytosis of oxidized low density lipoprotein through scavenger receptor CD36 utilizes a lipid raft pathway that does not require caveolin-1". J. Biol. Chem. 278 (46): 45931–6. doi:10.1074/jbc.M307722200. PMID 12947091.
- Pohl J, Ring A, Korkmaz U, Ehehalt R, Stremmel W (January 2005). "FAT/CD36-mediated long-chain fatty acid uptake in adipocytes requires plasma membrane rafts". Mol. Biol. Cell 16 (1): 24–31. doi:10.1091/mbc.E04-07-0616. PMC 539148. PMID 15496455.
- Daviet L, Malvoisin E, Wild TF, McGregor JL (August 1997). "Thrombospondin induces dimerization of membrane-bound, but not soluble CD36". Thromb. Haemost. 78 (2): 897–901. PMID 9268192.
- Fernández-Ruiz E, Armesilla AL, Sánchez-Madrid F, Vega MA (September 1993). "Gene encoding the collagen type I and thrombospondin receptor CD36 is located on chromosome 7q11.2". Genomics 17 (3): 759–61. doi:10.1006/geno.1993.1401. PMID 7503937.
- Collins RF, Touret N, Kuwata H, Tandon NN, Grinstein S, Trimble WS (September 2009). "Uptake of oxLDL by CD36 occurs by an actin-dependent pathway distinct from macropinocytosis". J. Biol. Chem. 284 (44): 30288–97. doi:10.1074/jbc.M109.045104. PMC 2781584. PMID 19740737.
- Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, Rayner KJ, Boyer L, Zhong R, Frazier WA, Lacy-Hulbert A, Khoury JE, Golenbock DT, Moore KJ (February 2010). "CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer". Nat. Immunol. 11 (2): 155–61. doi:10.1038/ni.1836. PMC 2809046. PMID 20037584.
- Kuda O, Jenkins CM, Skinner JR, Moon SH, Su X, Gross RW, Abumrad NA (May 2011). "CD36 Protein Is Involved in Store-operated Calcium Flux, Phospholipase A2 Activation, and Production of Prostaglandin E2". J Biol Chem. 286 (20): 17785–17795. doi:10.1074/jbc.M111.232975. PMID 21454644.
- Patel SN, Lu Z, Ayi K, Serghides L, Gowda DC, Kain KC (15 March 2007). "Disruption of CD36 impairs cytokine response to Plasmodium falciparum glycosylphosphatidylinositol and confers susceptibility to severe and fatal malaria in vivo". J. Immunol. 178 (6): 3954–61. PMID 17339496.
- Ikeda H, Mitani T, Ohnuma M, Haga H, Ohtzuka S, Kato T, Nakase T, Sekiguchi S (1989). "A new platelet-specific antigen, Naka, involved in the refractoriness of HLA-matched platelet transfusion". Vox Sang. 57 (3): 213–7. doi:10.1111/j.1423-0410.1989.tb00826.x. PMID 2617957.
- Yamamoto N, Ikeda H, Tandon NN, Herman J, Tomiyama Y, Mitani T, Sekiguchi S, Lipsky R, Kralisz U, Jamieson GA (November 1990). "A platelet membrane glycoprotein (GP) deficiency in healthy blood donors: Naka- platelets lack detectable GPIV (CD36)". Blood 76 (9): 1698–703. PMID 1699620.
- Ockenhouse CF, Klotz FW, Tandon NN, Jamieson GA (April 1991). "Sequestrin, a CD36 recognition protein on Plasmodium falciparum malaria-infected erythrocytes identified by anti-idiotype antibodies". Proc. Natl. Acad. Sci. U.S.A. 88 (8): 3175–9. doi:10.1073/pnas.88.8.3175. PMC 51408. PMID 1707534.
- Toba K, Hanawa H, Watanabe K, Fuse I, Masuko M, Miyajima S, Takahashi M, Sakaue M, Abo T, Aizawa Y (October 2001). "Erythroid involvement in CD36 deficiency". Exp. Hematol. 29 (10): 1194–200. doi:10.1016/S0301-472X(01)00691-9. PMID 11602321.
- Yanai H, Chiba H, Fujiwara H, Morimoto M, Abe K, Yoshida S, Takahashi Y, Fuda H, Hui SP, Akita H, Kobayashi K, Matsuno K (September 2000). "Phenotype-genotype correlation in CD36 deficiency types I and II". Thromb. Haemost. 84 (3): 436–41. PMID 11019968.
- Lee K, Godeau B, Fromont P, Plonquet A, Debili N, Bachir D, Reviron D, Gourin J, Fernandez E, Galactéros F, Bierling P (August 1999). "CD36 deficiency is frequent and can cause platelet immunization in Africans". Transfusion 39 (8): 873–9. doi:10.1046/j.1537-2995.1999.39080873.x. PMID 10504124.
- Curtis BR, Aster RH (April 1996). "Incidence of the Nak(a)-negative platelet phenotype in African Americans is similar to that of Asians". Transfusion 36 (4): 331–4. doi:10.1046/j.1537-2995.1996.36496226147.x. PMID 8623134.
- Bierling P, Godeau B, Fromont P, Bettaieb A, Debili N, el-Kassar N, Rouby JJ, Vainchenker W, Duedari N (September 1995). "Posttransfusion purpura-like syndrome associated with CD36 (Naka) isoimmunization". Transfusion 35 (9): 777–82. doi:10.1046/j.1537-2995.1995.35996029165.x. PMID 7570941.
- Pravenec M, Churchill PC, Churchill MC, Viklicky O, Kazdova L, Aitman TJ, Petretto E, Hubner N, Wallace CA, Zimdahl H, Zidek V, Landa V, Dunbar J, Bidani A, Griffin K, Qi N, Maxova M, Kren V, Mlejnek P, Wang J, Kurtz TW (August 2008). "Identification of renal Cd36 as a determinant of blood pressure and risk for hypertension". Nat. Genet. 40 (8): 952–4. doi:10.1038/ng.164. PMID 18587397.
- Okamoto F, Tanaka T, Sohmiya K, Kawamura K (July 1998). "CD36 abnormality and impaired myocardial long-chain fatty acid uptake in patients with hypertrophic cardiomyopathy". Jpn. Circ. J. 62 (7): 499–504. doi:10.1253/jcj.62.499. PMID 9707006.
- Philips JA, Rubin EJ, Perrimon N (August 2005). "Drosophila RNAi screen reveals CD36 family member required for mycobacterial infection". Science 309 (5738): 1251–3. doi:10.1126/science.1116006. PMID 16020694.
- Huang MM, Bolen JB, Barnwell JW, Shattil SJ, Brugge JS (September 1991). "Membrane glycoprotein IV (CD36) is physically associated with the Fyn, Lyn, and Yes protein-tyrosine kinases in human platelets". Proc. Natl. Acad. Sci. U.S.A. 88 (17): 7844–8. doi:10.1073/pnas.88.17.7844. PMC 52400. PMID 1715582.
- Bull HA, Brickell PM, Dowd PM (August 1994). "Src-related protein tyrosine kinases are physically associated with the surface antigen CD36 in human dermal microvascular endothelial cells". FEBS Lett. 351 (1): 41–4. doi:10.1016/0014-5793(94)00814-0. PMID 7521304.
Further reading 
- Febbraio M, Silverstein RL (2007). "CD36: implications in cardiovascular disease". Int. J. Biochem. Cell Biol. 39 (11): 2012–30. doi:10.1016/j.biocel.2007.03.012. PMC 2034445. PMID 17466567.
- Abumrad NA, Ajmal M, Pothakos K, Robinson JK (September 2005). "CD36 expression and brain function: does CD36 deficiency impact learning ability?". Prostaglandins Other Lipid Mediat. 77 (1-4): 77–83. doi:10.1016/j.prostaglandins.2004.09.012. PMID 16099393.
- Biello D (2005-11-02). "Potential Taste Receptor for Fat Identified". Scientific American. Retrieved 2008-08-05.