CD36
1149660
224256957
2008-07-08T00:56:16Z
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'''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 (biology)|cell]] surface proteins. CD36 binds many [[protein ligands|ligands]] including [[collagen]] <sup>[1]</sup>, [[thrombospondin]] <sup>[2]</sup>, [[erythrocyte]]s parasitized with ''[[Plasmodium falciparum]]'' <sup>[3]</sup>, oxidized [[low density lipoprotein]] <sup>[4]</sup>, native [[lipoproteins]] <sup>[5]</sup>, oxidized [[phospholipids]] <sup>[6]</sup> and long-chain [[fatty acid]]s <sup>[7]</sup>. Recent work using genetically modified rodents have identified a clear role for CD36 in [[fatty acid]] and [[glucose]] metabolism <sup>[8], [9]</sup>, [[heart disease]] <sup>[10]</sup>, taste <sup>[11]</sup> and dietary fat processing in the [[intestine]] <sup>[12]</sup>. It may be involved in glucose intolerance, [[atherosclerosis]], arterial [[hypertension]], [[diabetes]], [[cardiomyopathy]] and [[Alzheimer's disease]]. <ref name=rac2007> Rać ME, Safranow K, Poncyljusz W. 2007. Molecular basis of human CD36 gene mutation. Mol Med.</ref>
== Protein Structure and Classification ==
[[Image:CD36-in-membrane.png|frame|right|Fig. 1. Predicted [[membrane topology|topology]] of CD36 in the [[plasma membrane]].]]
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 [[Atomic mass unit|Da]]. However, CD36 is extensively glycosylated and has an apparent molecular weight of 88,000 [[Atomic mass unit|Da]] as determined by [[SDS-PAGE|SDS polyacrylamide gel electrophoresis]] <sup>[13]</sup>.
Using Kyte-Doolittle analysis <sup>[14]</sup>, the [[peptide sequence|amino acid sequence]] of CD36 precincts a [[hydrophobic]] region near each end of the protein large enough to span [[cell membrane|cellular membrane]]s. 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 [[alpha helix|α-helices]] at the C- and N- termini projecting through the [[cell membrane|membrane]] and a larger extracellular loop (Fig. 1). This [[membrane topology|topology]] is supported by transfection experiments in cultured cells using deletion mutants of CD36 <sup>[15], [16]</sup>. Unlike the topology and proposed structure of transmembrane [[alpha helix|α-helices]], very little is known about the [[secondary structure]] of the extracellular loop.
Besides glycosylation, additional [[posttranslational modification]]s 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]] <sup>[17]</sup>. It is not clear what role these linkages play on the function of the mature CD36 protein on the cell surface. CD36 is also [[posttranslational modification|posttranslationally]] modified with 4 [[palmitoyl chains]], 2 on each of the two intracellular domains <sup>[16]</sup>. 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 <sup>[18], [19]</sup>.
==== Planned additions to this section ====
Protein-protein interactions. Note <sup>[20]</sup> on homooligomerization.
== Genetics, Gene Expression and Regulation ==
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CD36 is found on [[platelet]]s, [[erythrocyte]]s, [[monocyte]]s, differentiated [[adipocyte]]s, [[mammary epithelial cell]]s, [[spleen]] cells and some [[skin]] microdermal [[endothelial cell]]s.
The [[gene]] is located on the long arm of [[chromosome]] 7 at band 11.2 (7q11.2 <sup>[21]</sup>) and is encoded by 15 [[exon]]s that extend over more than 32 [[kilobase]]s. Both the 5' and the 3' untranslated regions contain [[intron]]s: 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 (genetics)|transcription]] initiation site of the CD36 gene has been mapped to 289 [[nucleotide]]s 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 [[cell nucleus|nuclear]] [[receptor (biochemistry)|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 [[medication|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]]/[[wiktionary:schizont|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 [[gametocyte]]s (stages I and II).
CD36 has been shown to have a role in the innate immune response to malaria in mouse models. <ref name="Patel2007"> Patel SN, Lu Z, Ayi K, Serghides L, Gowda DC, Kain KC. (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):3954-3961 </ref>. 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]], [[erythrocyte]]s parasitized with ''[[Plasmodium falciparum]]'', [[platelet-agglutinating protein p37]], oxidized [[low density lipoprotein]] and [[long-chain fatty acid]]s. 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.<ref name="Pravenec2008"> Pravenec M., Churchill P.C., Churchill M.C., Viklicky O., Kazdova L., Aitman T.J., Petretto E., Hubner N., Wallace C.A., Zimdahl H., Zidek V., Landa V., Dunbar J., Bidani A., Griffin K., Qi N., Maxova M., Kren V., Mlejnek P., Wang J., Kurtz T.W. (2008) Identification of renal CD36 as a determinant of blood pressure and risk for hypertension. Nat. Genet. </ref>
== CD36 Deficiency and Alloimmune Thrombocytopenia ==
Mutations in the human CD36 gene were first identified in a patient who, despite multiple [[platelet]] [[blood transfusions|transfusions]], continued to exhibit low platelet levels <sup>[22], [23]</sup>. 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 <sup>[24]</sup>
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 [[Africa]]n (2.5%), [[Japan]]ese, and other [[Asia]]n populations (5-11%). The molecular basis is known for some cases: T1264G in both [[Kenya]]ns and [[Gambia]]ns; 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.
==External links==
*[http://www.sciam.com/article.cfm?chanID=sa003&articleID=000AFE88-E770-1367-A6B083414B7F4945 Scientific American article: "Potential Taste Receptor for Fat Identified"]
==References==
{{Reflist}}
{{refbegin}}
#[[Image:Free text.png]] Identification of glycoprotein IV (CD36) as a primary receptor for platelet-collagen adhesion. ''1989 May 5; {{PMID|2468670}}'' [http://www.jbc.org/cgi/reprint/264/13/7576 Free text (PDF - 980K)]
#[[Image:Free text.png]] Sense and antisense cDNA transfection of CD36 (glycoprotein IV) in melanoma cells. Role of CD36 as a thrombospondin receptor. ''1992 Aug 15; {{PMID|1379600}}'' [http://www.jbc.org/cgi/reprint/267/23/16607 Free text (PDF - 1.6M)]
#CD36 directly mediates cytoadherence of Plasmodium falciparum parasitized erythrocytes. ''1989 Jul 14; {{PMID|2473841}}''
#[[Image:Free text.png]] 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; {{PMID|7538425}}'' [http://atvb.ahajournals.org/cgi/content/full/15/2/269 Free text]
#[[Image:Free text.png]] Human CD36 is a high affinity receptor for the native lipoproteins HDL, LDL, and VLDL. ''1998 Apr; {{PMID|9555943}}'' [http://www.jlr.org/cgi/content/full/39/4/777 Free text]
#[[Image:Free text.png]] Identification of a novel family of oxidized phospholipids that serve as ligands for the macrophage scavenger receptor CD36. ''2002 Oct 11; {{PMID|12105195}}'' [http://www.jbc.org/cgi/content/full/277/41/38503 Free text]
#[[Image:Free text.png]] Reversible binding of long-chain fatty acids to purified FAT, the adipose CD36 homolog. ''1996 Sep; {{PMID|8694909}}'' [http://www.springerlink.com/(1kw41x45hruxlursqoxgqo55)/app/home/content.asp?referrer=contribution&format=2&page=1&pagecount=7 Free text (PDF - 202K)]
#[[Image:Free text.png]] Defective fatty acid uptake modulates insulin responsiveness and metabolic responses to diet in CD36-null mice. ''2002 May; {{PMID|12021254}}'' {{PMID_free|12021254}}
#[[Image:Free text.png]] Transgenic expression of CD36 in the spontaneously hypertensive rat is associated with amelioration of metabolic disturbances but has no effect on hypertension. ''2003; {{PMID|14640889}}'' [http://www.ncbi.nlm.nih.gov/entrez/utils/lofref.fcgi?PrId=4130&uid=14640889&db=pubmed&url=http://www.biomed.cas.cz/physiolres/pdf/2003/52_681.pdf Free text (PDF - 146K)]
#[[Image:Free text.png]] Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice. ''2000 Apr; {{PMID|10772649}}'' {{PMID_free|10772649}}
#[[Image:Free text.png]] CD36 involvement in orosensory detection of dietary lipids, spontaneous fat preference, and digestive secretions. ''2005 Nov; {{PMID|16276419}}'' {{PMID_free|16276419}}
#[[Image:Free text.png]] CD36 deficiency impairs intestinal lipid secretion and clearance of chylomicrons from the blood. ''2005 May; {{PMID|15841205}}'' {{PMID_free|15841205}}
#PAS IV, an integral membrane protein of mammary epithelial cells, is related to platelet and endothelial cell CD36 (GP IV). ''1990 Jul 31; {{PMID|1699598}}''
#A simple method for displaying the hydropathic character of a protein. ''1982 May 5; {{PMID|7108955}}''
#CD36 is a ditopic glycoprotein with the N-terminal domain implicated in intracellular transport. ''2000 Aug 28; {{PMID|10964685}}''
#[[Image:Free text.png]] CD36 is palmitoylated on both N- and C-terminal cytoplasmic tails. ''1996 Sep 13: {{PMID|8798390}}'' [http://www.jbc.org/cgi/content/full/271/37/22315 Free text]
#[[Image:Free text.png]] Formation of one or more intrachain disulfide bonds is required for the intracellular processing and transport of CD36. ''1997 Dec 1; {{PMID|9371725}}'' {{PMID_free|9371725}}
#[[Image:Free text.png]] Endocytosis of oxidized low density lipoprotein through scavenger receptor CD36 utilizes a lipid raft pathway that does not require caveolin-1. ''2003 Nov 14; {{PMID|12947091}}'' [http://www.jbc.org/cgi/content/full/278/46/45931 Free text]
#[[Image:Free text.png]] FAT/CD36-mediated long-chain fatty acid uptake in adipocytes requires plasma membrane rafts. ''2005 Jan; {{PMID|15496455}}'' {{PMID_free|15496455}}
#Thrombospondin induces dimerization of membrane-bound, but not soluble CD36. ''1997 Aug; {{PMID|9268192}}''
#Gene encoding the collagen type I and thrombospondin receptor CD36 is located on chromosome 7q11.2. ''1993 Sep; {{PMID|7503937}}''
#A new platelet-specific antigen, Naka, involved in the refractoriness of HLA-matched platelet transfusion. ''1989; {{PMID|2617957}}''
#[[Image:Free text.png]] A platelet membrane glycoprotein (GP) deficiency in healthy blood donors: Naka- platelets lack detectable GPIV (CD36). ''1990 Nov 1; {{PMID|1699620}}'' [http://www.bloodjournal.org/cgi/reprint/76/9/1698 Free text (PDF - 2.4M)]
#[[Image:Free text.png]] CD36 abnormality and impaired myocardial long-chain fatty acid uptake in patients with hypertrophic cardiomyopathy. ''1998 Jul; {{PMID|9707006}}'' [http://www.jstage.jst.go.jp/article/jcj/62/7/499/_pdf Free text (PDF - 300K)]
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== Further reading ==
{{refbegin}}
* Febbraio M, Silverstein RL. (2007) CD36: Implications in cardiovascular disease. Int. J. Biochem. Cell. Biol. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17466567&query_hl=1&itool=pubmed_docsum]
{{PBB_Further_reading
| citations =
*{{cite journal | author=Abumrad NA, Ajmal M, Pothakos K, Robinson JK |title=CD36 expression and brain function: does CD36 deficiency impact learning ability? |journal=Prostaglandins Other Lipid Mediat. |volume=77 |issue= 1-4 |pages= 77–83 |year= 2005 |pmid= 16099393 |doi= 10.1016/j.prostaglandins.2004.09.012 }}
}}
{{refend}}
{{Clusters of differentiation}}
{{Membrane transport proteins}}
[[Category:Clusters of differentiation]]
[[Category:Proteins]]
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