CD36

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,cite journal | author = Tandon NN, Kralisz U, Jamieson GA | title = Identification of glycoprotein IV (CD36) as a primary receptor for platelet-collagen adhesion | journal = J. Biol. Chem. | volume = 264 | issue = 13 | pages = 7576–83 | year = 1989 | month = May | pmid = 2468670 | url = http://www.jbc.org/cgi/pmidlookup?view=long&pmid=2468670 | issn = ] thrombospondin,cite journal | author = Silverstein RL, Baird M, Lo SK, Yesner LM | title = Sense and antisense cDNA transfection of CD36 (glycoprotein IV) in melanoma cells. Role of CD36 as a thrombospondin receptor | journal = J. Biol. Chem. | volume = 267 | issue = 23 | pages = 16607–12 | year = 1992 | month = August | pmid = 1379600 | url = http://www.jbc.org/cgi/pmidlookup?view=long&pmid=1379600 | issn = ] erythrocytes parasitized with "Plasmodium falciparum",cite journal | author = Oquendo P, Hundt E, Lawler J, Seed B | title = CD36 directly mediates cytoadherence of Plasmodium falciparum parasitized erythrocytes | journal = Cell | volume = 58 | issue = 1 | pages = 95–101 | year = 1989 | month = July | pmid = 2473841 | url = | doi = 10.1016/0092-8674(89)90406-6 ] oxidized low density lipoprotein,cite journal | author = Nicholson AC, Frieda S, Pearce A, Silverstein RL | title = 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 | journal = Arterioscler. Thromb. Vasc. Biol. | volume = 15 | issue = 2 | pages = 269–75 | year = 1995 | month = February | pmid = 7538425 | url = http://atvb.ahajournals.org/cgi/pmidlookup?view=long&pmid=7538425 | issn = ] native lipoproteins,cite journal | author = Calvo D, Gómez-Coronado D, Suárez Y, Lasunción MA, Vega MA | title = Human CD36 is a high affinity receptor for the native lipoproteins HDL, LDL, and VLDL | journal = J. Lipid Res. | volume = 39 | issue = 4 | pages = 777–88 | year = 1998 | month = April | pmid = 9555943 | url = http://www.jlr.org/cgi/pmidlookup?view=long&pmid=9555943 | issn = ] oxidized phospholipids,cite journal | author = 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 | title = Identification of a novel family of oxidized phospholipids that serve as ligands for the macrophage scavenger receptor CD36 | journal = J. Biol. Chem. | volume = 277 | issue = 41 | pages = 38503–16 | year = 2002 | month = October | pmid = 12105195 | doi = 10.1074/jbc.M203318200 | url = ] and long-chain fatty acids.cite journal | author = Baillie AG, Coburn CT, Abumrad NA | title = Reversible binding of long-chain fatty acids to purified FAT, the adipose CD36 homolog | journal = J. Membr. Biol. | volume = 153 | issue = 1 | pages = 75–81 | year = 1996 | month = September | pmid = 8694909 | url = | doi = 10.1007/s002329900111 ]

Recent work using genetically modified rodents have identified a clear role for CD36 in fatty acid and glucose metabolism,cite journal | author = Hajri T, Han XX, Bonen A, Abumrad NA | title = Defective fatty acid uptake modulates insulin responsiveness and metabolic responses to diet in CD36-null mice | journal = J. Clin. Invest. | volume = 109 | issue = 10 | pages = 1381–9 | year = 2002 | month = May | pmid = 12021254 | pmc = 150975 | doi = 10.1172/JCI14596 | url = ] cite journal | author = Pravenec M, Landa V, Zídek V, Musilová A, Kazdová L, Qi N, Wang J, St Lezin E, Kurtz TW | title = Transgenic expression of CD36 in the spontaneously hypertensive rat is associated with amelioration of metabolic disturbances but has no effect on hypertension | journal = Physiol Res | volume = 52 | issue = 6 | pages = 681–8 | year = 2003 | pmid = 14640889 | url = http://www.biomed.cas.cz/physiolres/pdf/52/52_681.pdf | issn = ] heart disease,cite journal | author = Febbraio M, Podrez EA, Smith JD, Hajjar DP, Hazen SL, Hoff HF, Sharma K, Silverstein RL | title = Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice | journal = J. Clin. Invest. | volume = 105 | issue = 8 | pages = 1049–56 | year = 2000 | month = April | pmid = 10772649 | pmc = 300837 | doi = 10.1172/JCI9259 | url = ] taste,cite journal | author = Laugerette F, Passilly-Degrace P, Patris B, Niot I, Febbraio M, Montmayeur JP, Besnard P | title = CD36 involvement in orosensory detection of dietary lipids, spontaneous fat preference, and digestive secretions | journal = J. Clin. Invest. | volume = 115 | issue = 11 | pages = 3177–84 | year = 2005 | month = November | pmid = 16276419 | pmc = 1265871 | doi = 10.1172/JCI25299 | url = ] and dietary fat processing in the intestine.cite journal | author = Drover VA, Ajmal M, Nassir F, Davidson NO, Nauli AM, Sahoo D, Tso P, Abumrad NA | title = CD36 deficiency impairs intestinal lipid secretion and clearance of chylomicrons from the blood | journal = J. Clin. Invest. | volume = 115 | issue = 5 | pages = 1290–7 | year = 2005 | month = May | pmid = 15841205 | pmc = 1074677 | doi = 10.1172/JCI21514 | url = ] It may be involved in glucose intolerance, atherosclerosis, arterial hypertension, diabetes, cardiomyopathy and Alzheimer's disease.cite journal | author = Rać ME, Safranow K, Poncyljusz W | title = Molecular basis of human CD36 gene mutations | journal = Mol. Med. | volume = 13 | issue = 5-6 | pages = 288–96 | year = 2007 | pmid = 17673938 | pmc = 1936231 | doi = 10.2119/2006–00088.Raæ | url = | doi_brokendate = 2008-08-05 ]

Structure

Primary

In [http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NP_000063.2 humans] , [http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NP_113749.2 rats] and [http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NP_031669.2 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.cite journal | author = Greenwalt DE, Watt KW, So OY, Jiwani N | title = PAS IV, an integral membrane protein of mammary epithelial cells, is related to platelet and endothelial cell CD36 (GP IV) | journal = Biochemistry | volume = 29 | issue = 30 | pages = 7054–9 | year = 1990 | month = July | pmid = 1699598 | url = | doi = 10.1021/bi00482a015 ]

Tertiary

Using Kyte-Doolittle analysis,cite journal | author = Kyte J, Doolittle RF | title = A simple method for displaying the hydropathic character of a protein | journal = J. Mol. Biol. | volume = 157 | issue = 1 | pages = 105–32 | year = 1982 | month = May | pmid = 7108955 | url = http://linkinghub.elsevier.com/retrieve/pii/0022-2836(82)90515-0 | issn = ] 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.cite journal | author = Gruarin P, Thorne RF, Dorahy DJ, Burns GF, Sitia R, Alessio M | title = CD36 is a ditopic glycoprotein with the N-terminal domain implicated in intracellular transport | journal = Biochem. Biophys. Res. Commun. | volume = 275 | issue = 2 | pages = 446–54 | year = 2000 | month = August | pmid = 10964685 | doi = 10.1006/bbrc.2000.3333 | url = ] cite journal | author = Tao N, Wagner SJ, Lublin DM | title = CD36 is palmitoylated on both N- and C-terminal cytoplasmic tails | journal = J. Biol. Chem. | volume = 271 | issue = 37 | pages = 22315–20 | year = 1996 | month = September | pmid = 8798390 | url = | doi = 10.1074/jbc.271.37.22315 ]

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.cite journal | author = Gruarin P, Sitia R, Alessio M | title = Formation of one or more intrachain disulphide bonds is required for the intracellular processing and transport of CD36 | journal = Biochem. J. | volume = 328 ( Pt 2) | issue = | pages = 635–42 | year = 1997 | month = December | pmc = 1218965 | pmid = 9371725 | url = | issn = ] 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.cite journal | author = Zeng Y, Tao N, Chung KN, Heuser JE, Lublin DM | title = Endocytosis of oxidized low density lipoprotein through scavenger receptor CD36 utilizes a lipid raft pathway that does not require caveolin-1 | journal = J. Biol. Chem. | volume = 278 | issue = 46 | pages = 45931–6 | year = 2003 | month = November | pmid = 12947091 | doi = 10.1074/jbc.M307722200 | url = ] cite journal | author = Pohl J, Ring A, Korkmaz U, Ehehalt R, Stremmel W | title = FAT/CD36-mediated long-chain fatty acid uptake in adipocytes requires plasma membrane rafts | journal = Mol. Biol. Cell | volume = 16 | issue = 1 | pages = 24–31 | year = 2005 | month = January | pmid = 15496455 | pmc = 539148 | doi = 10.1091/mbc.E04-07-0616 | url = ]

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.cite journal | author = Daviet L, Malvoisin E, Wild TF, McGregor JL | title = Thrombospondin induces dimerization of membrane-bound, but not soluble CD36 | journal = Thromb. Haemost. | volume = 78 | issue = 2 | pages = 897–901 | year = 1997 | month = August | pmid = 9268192 | url = | issn = ]

Genetics

The gene is located on the long arm of chromosome 7 at band 11.2 (7q11.2cite journal | author = Fernández-Ruiz E, Armesilla AL, Sánchez-Madrid F, Vega MA | title = Gene encoding the collagen type I and thrombospondin receptor CD36 is located on chromosome 7q11.2 | journal = Genomics | volume = 17 | issue = 3 | pages = 759–61 | year = 1993 | month = September | pmid = 7503937 | doi = 10.1006/geno.1993.1401 | url = ] ) 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

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

Function

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.

This gene has also been implicated in the control of blood pressure.cite journal | author = 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 | title = Identification of renal Cd36 as a determinant of blood pressure and risk for hypertension | journal = Nat. Genet. | volume = 40 | issue = 8 | pages = 952–4 | year = 2008 | month = August | pmid = 18587397 | doi = 10.1038/ng.164 | url = ]

An association with myocardial fatty acid uptake in humans has been noted.cite journal | author = Okamoto F, Tanaka T, Sohmiya K, Kawamura K | title = CD36 abnormality and impaired myocardial long-chain fatty acid uptake in patients with hypertrophic cardiomyopathy | journal = Jpn. Circ. J. | volume = 62 | issue = 7 | pages = 499–504 | year = 1998 | month = July | pmid = 9707006 | url = | doi = 10.1253/jcj.62.499 ] The data suggest a link between hypertrophic cardiomyopathy and CD36 but this needs to be confirmed.

Clinical significance

Malaria

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/ 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.cite journal | author = Patel SN, Lu Z, Ayi K, Serghides L, Gowda DC, Kain KC | title = Disruption of CD36 impairs cytokine response to Plasmodium falciparum glycosylphosphatidylinositol and confers susceptibility to severe and fatal malaria in vivo | journal = J. Immunol. | volume = 178 | issue = 6 | pages = 3954–61 | year = 2007 | month = March | pmid = 17339496 | url = http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=17339496 | issn = ] 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.

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.cite journal | author = Ikeda H, Mitani T, Ohnuma M, Haga H, Ohtzuka S, Kato T, Nakase T, Sekiguchi S | title = A new platelet-specific antigen, Naka, involved in the refractoriness of HLA-matched platelet transfusion | journal = Vox Sang. | volume = 57 | issue = 3 | pages = 213–7 | year = 1989 | pmid = 2617957 | url = | issn = ] cite journal | author = Yamamoto N, Ikeda H, Tandon NN, Herman J, Tomiyama Y, Mitani T, Sekiguchi S, Lipsky R, Kralisz U, Jamieson GA | title = A platelet membrane glycoprotein (GP) deficiency in healthy blood donors: Naka- platelets lack detectable GPIV (CD36) | journal = Blood | volume = 76 | issue = 9 | pages = 1698–703 | year = 1990 | month = November | pmid = 1699620 | doi = | url = http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=1699620 | issn = ] 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.cite journal | author = Ockenhouse CF, Klotz FW, Tandon NN, Jamieson GA | title = Sequestrin, a CD36 recognition protein on Plasmodium falciparum malaria-infected erythrocytes identified by anti-idiotype antibodies | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 88 | issue = 8 | pages = 3175–9 | year = 1991 | month = April | pmid = 1707534 | pmc = 51408 | url = | doi = 10.1073/pnas.88.8.3175 ]

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 in to 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.cite journal | author = Toba K, Hanawa H, Watanabe K, Fuse I, Masuko M, Miyajima S, Takahashi M, Sakaue M, Abo T, Aizawa Y | title = Erythroid involvement in CD36 deficiency | journal = Exp. Hematol. | volume = 29 | issue = 10 | pages = 1194–200 | year = 2001 | month = October | pmid = 11602321 | url = http://linkinghub.elsevier.com/retrieve/pii/S0301-472X(01)00691-9 | doi = 10.1016/S0301-472X(01)00691-9 ] 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.cite journal | author = Yanai H, Chiba H, Fujiwara H, Morimoto M, Abe K, Yoshida S, Takahashi Y, Fuda H, Hui SP, Akita H, Kobayashi K, Matsuno K | title = Phenotype-genotype correlation in CD36 deficiency types I and II | journal = Thromb. Haemost. | volume = 84 | issue = 3 | pages = 436–41 | year = 2000 | month = September | pmid = 11019968 | url = http://www.schattauer.de/index.php?id=1268&pii=th00090436&no_cache=1 | issn = ] In 1127 healthy French blood donors (almost all of whom were white Europeans) no CD36 deficiency was found.cite journal | author = Lee K, Godeau B, Fromont P, Plonquet A, Debili N, Bachir D, Reviron D, Gourin J, Fernandez E, Galactéros F, Bierling P | title = CD36 deficiency is frequent and can cause platelet immunization in Africans | journal = Transfusion | volume = 39 | issue = 8 | pages = 873–9 | year = 1999 | month = August | pmid = 10504124 | url = | doi = 10.1046/j.1537-2995.1999.39080873.x ] 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.cite journal | author = Curtis BR, Aster RH | title = Incidence of the Nak(a)-negative platelet phenotype in African Americans is similar to that of Asians | journal = Transfusion | volume = 36 | issue = 4 | pages = 331–4 | year = 1996 | month = April | pmid = 8623134 | url = | doi = 10.1046/j.1537-2995.1996.36496226147.x ]

CD36 deficiency may be a cause of post transfusion purpura.cite journal | author = Bierling P, Godeau B, Fromont P, Bettaieb A, Debili N, el-Kassar N, Rouby JJ, Vainchenker W, Duedari N | title = Posttransfusion purpura-like syndrome associated with CD36 (Naka) isoimmunization | journal = Transfusion | volume = 35 | issue = 9 | pages = 777–82 | year = 1995 | month = September | pmid = 7570941 | doi = | url = | issn = ]

ee also

* Cluster of differentiation

References

Further reading

*
*

External links

*

PBB_Controls
update_page = yes
require_manual_inspection = no
update_protein_box = yes
update_summary = no
update_citations = yes