Editing CD36

{{cs1 config|name-list-style=vanc}}
{{Short description|Mammalian protein found in humans}}
{{Infobox_gene}}

'''CD36''' ([[cluster of differentiation]] 36), also known as '''platelet glycoprotein 4''', '''fatty acid translocase''' ('''FAT'''), scavenger receptor class B member 3 ('''SCARB3'''), and glycoproteins 88 ('''GP88'''), IIIb ('''GPIIIB'''), or IV ('''GPIV''') is a [[protein]] that in humans is encoded by the ''CD36'' [[gene]]. The CD36 antigen is an [[integral membrane protein]] found on the surface of many cell types in vertebrate animals. It imports fatty acids inside cells and is a member of the class B [[scavenger receptor (immunology)|scavenger receptor]] family of [[cell (biology)|cell]] surface proteins. CD36 binds many [[protein ligands|ligands]] including [[collagen]],<ref name="pmid2468670">{{cite journal | vauthors = Tandon NN, Kralisz U, Jamieson GA | title = Identification of glycoprotein IV (CD36) as a primary receptor for platelet-collagen adhesion | journal = The Journal of Biological Chemistry | volume = 264 | issue = 13 | pages = 7576–83 | date = May 1989 | doi = 10.1016/S0021-9258(18)83273-2 | pmid = 2468670 | doi-access = free }}</ref> [[thrombospondin]],<ref name="pmid1379600">{{cite journal | vauthors = 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 = The Journal of Biological Chemistry | volume = 267 | issue = 23 | pages = 16607–12 | date = August 1992 | doi = 10.1016/S0021-9258(18)42046-7 | pmid = 1379600 | doi-access = free }}</ref> [[erythrocyte]]s parasitized with ''[[Plasmodium falciparum]]'',<ref name="pmid2473841">{{cite journal | vauthors = 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 | date = July 1989 | pmid = 2473841 | doi = 10.1016/0092-8674(89)90406-6 | s2cid = 22059108 }}</ref> oxidized [[low density lipoprotein]],<ref name="pmid7685021">{{cite journal | vauthors = Endemann G, Stanton LW, Madden KS, Bryant CM, White RT, Protter AA | title = CD36 is a receptor for oxidized low density lipoprotein | journal = The Journal of Biological Chemistry | volume = 268 | issue = 16 | pages = 11811–6 | date = June 1993 | doi = 10.1016/S0021-9258(19)50272-1 | pmid = 7685021 | doi-access = free }}</ref><ref name="pmid7538425">{{cite journal | vauthors = 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 = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 15 | issue = 2 | pages = 269–75 | date = February 1995 | pmid = 7538425 | doi = 10.1161/01.ATV.15.2.269 | doi-access = free }}</ref> native [[lipoproteins]],<ref name="pmid9555943">{{cite journal | vauthors = 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 = Journal of Lipid Research | volume = 39 | issue = 4 | pages = 777–88 | date = April 1998 | doi = 10.1016/S0022-2275(20)32566-9 | pmid = 9555943 | url = http://www.jlr.org/cgi/pmidlookup?view=long&pmid=9555943 | archive-url = https://archive.today/20130415062705/http://www.jlr.org/cgi/pmidlookup?view=long&pmid=9555943 | url-status = dead | archive-date = April 15, 2013 | doi-access = free }}</ref> oxidized [[phospholipids]],<ref name="pmid12105195">{{cite journal | vauthors = 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 | display-authors = 6 | title = Identification of a novel family of oxidized phospholipids that serve as ligands for the macrophage scavenger receptor CD36 | journal = The Journal of Biological Chemistry | volume = 277 | issue = 41 | pages = 38503–16 | date = October 2002 | pmid = 12105195 | doi = 10.1074/jbc.M203318200 | doi-access = free }}</ref> and long-chain [[fatty acid]]s.<ref name="pmid8694909">{{cite journal | vauthors = Baillie AG, Coburn CT, Abumrad NA |author3-link=Nada Abumrad | title = Reversible binding of long-chain fatty acids to purified FAT, the adipose CD36 homolog | journal = The Journal of Membrane Biology | volume = 153 | issue = 1 | pages = 75–81 | date = September 1996 | pmid = 8694909 | doi = 10.1007/s002329900111 | s2cid = 5911289 }}</ref>

Work in genetically modified rodents suggest a role for CD36 in [[fatty acid]] metabolism,<ref name="pmid12021254">{{cite journal | vauthors = 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 = The Journal of Clinical Investigation | volume = 109 | issue = 10 | pages = 1381–9 | date = May 2002 | pmid = 12021254 | pmc = 150975 | doi = 10.1172/JCI14596 }}</ref><ref name="pmid14640889">{{cite journal | vauthors = Pravenec M, Landa V, Zídek V, Musilová A, Kazdová L, Qi N, Wang J, St Lezin E, Kurtz TW | display-authors = 6 | title = Transgenic expression of CD36 in the spontaneously hypertensive rat is associated with amelioration of metabolic disturbances but has no effect on hypertension | journal = Physiological Research | volume = 52 | issue = 6 | pages = 681–8 | year = 2003 | doi = 10.33549/physiolres.930380 | pmid = 14640889 | url = http://www.biomed.cas.cz/physiolres/pdf/52/52_681.pdf }}</ref><ref name="pmid34880245">{{cite journal | vauthors = Mistry JJ, Bowles KM, Rushworth SA | title = Free fatty-acid transport via CD36 drives β-oxidation-mediated hematopoietic stem cell response to infection | journal = Nature Communications | volume = 12 | issue = 1 | date = December 2021 | page = 7130 | pmid = 34880245 | doi = 10.1038/s41467-021-27460-9 | pmc = 8655073 | bibcode = 2021NatCo..12.7130M }}</ref> [[heart disease]],<ref name="pmid10772649">{{cite journal | vauthors = Febbraio M, Podrez EA, Smith JD, Hajjar DP, Hazen SL, Hoff HF, Sharma K, Silverstein RL | display-authors = 6 | title = Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice | journal = The Journal of Clinical Investigation | volume = 105 | issue = 8 | pages = 1049–56 | date = April 2000 | pmid = 10772649 | pmc = 300837 | doi = 10.1172/JCI9259 }}</ref> taste,<ref name="pmid16276419">{{cite journal | vauthors = 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 = The Journal of Clinical Investigation | volume = 115 | issue = 11 | pages = 3177–84 | date = November 2005 | pmid = 16276419 | pmc = 1265871 | doi = 10.1172/JCI25299 }}</ref><ref name="Pepino_2012">{{cite journal | vauthors = Pepino MY, Love-Gregory L, Klein S, Abumrad NA | title = The fatty acid translocase gene CD36 and lingual lipase influence oral sensitivity to fat in obese subjects | journal = Journal of Lipid Research | volume = 53 | issue = 3 | pages = 561–6 | date = March 2012 | pmid = 22210925 | pmc = 3276480 | doi = 10.1194/jlr.M021873  |doi-access=free }}</ref><ref name="pmid24631296">{{cite journal | vauthors = DiPatrizio NV | title = Is fat taste ready for primetime? | journal = Physiology & Behavior | volume = 136 | pages = 145–54 | date = September 2014 | pmid = 24631296 | pmc = 4162865 | doi = 10.1016/j.physbeh.2014.03.002 }}</ref> and dietary fat processing in the [[intestine]].<ref name="pmid15841205">{{cite journal | vauthors = Drover VA, Ajmal M, Nassir F, Davidson NO, Nauli AM, Sahoo D, Tso P, Abumrad NA | display-authors = 6 | title = CD36 deficiency impairs intestinal lipid secretion and clearance of chylomicrons from the blood | journal = The Journal of Clinical Investigation | volume = 115 | issue = 5 | pages = 1290–7 | date = May 2005 | pmid = 15841205 | pmc = 1074677 | doi = 10.1172/JCI21514 }}</ref> It may be involved in [[glucose intolerance]], [[atherosclerosis]], arterial [[hypertension]], [[diabetes]], [[cardiomyopathy]], [[Alzheimer's disease]] and various [[cancers]], mostly of [[epithelium|epithelial origin]] ([[breast cancer|breast]], [[prostate cancer|prostate]], [[ovary cancer|ovary]], and [[colon cancer|colon]]) and also for [[hepatic carcinoma]] and [[gliomas]].<ref name="pmid17673938">{{cite journal | vauthors = Rać ME, Safranow K, Poncyljusz W | title = Molecular basis of human CD36 gene mutations | journal = Molecular Medicine | volume = 13 | issue = 5–6 | pages = 288–96 | year = 2007 | pmid = 17673938 | pmc = 1936231 | doi = 10.2119/2006-00088.Rac }}</ref><ref name="pmid30069479">{{cite journal | author1 = Ana-Maria Enciu | author2 = Eugen Radu | author3 = Ionela Daniela Popescu | author4 = Mihail Eugen Hinescu | author5 = Laura Cristina Ceafalan | title = Targeting CD36 as Biomarker for Metastasis Prognostic: How Far from Translation into Clinical Practice? | journal = BioMed Research International | volume = 2018 | year = 2018 | pages = 1–12 | pmid = 30069479 | pmc = 6057354 | doi = 10.1155/2018/7801202 | doi-access = free }}</ref><ref name="pmid31410189">{{cite journal | author1 = Jingchun Wang | author2 = Yongsheng Li | title = CD36 tango in cancer: signaling pathways and functions | journal = Theranostics | volume = 9 | issue = 17 | pages = 4893–490 | year = 2019 | pmid = 31410189 | pmc = 6691380 | doi = 10.7150/thno.36037 }}</ref>

== Structure ==

=== Primary ===

In [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NP_000063.2 humans], [https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NP_113749.2 rats] and [https://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]].<ref name="pmid1699598">{{cite journal | vauthors = 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 | date = July 1990 | pmid = 1699598 | doi = 10.1021/bi00482a015 }}</ref>

=== Tertiary ===

Using [[Hydrophobicity scales|Kyte–Doolittle analysis]],<ref name="pmid7108955">{{cite journal | vauthors = Kyte J, Doolittle RF | title = A simple method for displaying the hydropathic character of a protein | journal = Journal of Molecular Biology | volume = 157 | issue = 1 | pages = 105–32 | date = May 1982 | pmid = 7108955 | doi = 10.1016/0022-2836(82)90515-0 | citeseerx = 10.1.1.458.454 }}</ref> the [[peptide sequence|amino acid sequence]] of CD36 predicts 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.<ref name="pmid10964685">{{cite journal | vauthors = 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 = Biochemical and Biophysical Research Communications | volume = 275 | issue = 2 | pages = 446–54 | date = August 2000 | pmid = 10964685 | doi = 10.1006/bbrc.2000.3333 }}</ref><ref name="pmid8798390">{{cite journal | vauthors = Tao N, Wagner SJ, Lublin DM | title = CD36 is palmitoylated on both N- and C-terminal cytoplasmic tails | journal = The Journal of Biological Chemistry | volume = 271 | issue = 37 | pages = 22315–20 | date = September 1996 | pmid = 8798390 | doi = 10.1074/jbc.271.37.22315 | doi-access = free }}</ref>

Based on the crystal structure of the homologous [[SCARB2]], a model of the extracellular domain of CD36 has been produced.<ref>{{cite journal | vauthors = Neculai D, Schwake M, Ravichandran M, Zunke F, Collins RF, Peters J, Neculai M, Plumb J, Loppnau P, Pizarro JC, Seitova A, Trimble WS, Saftig P, Grinstein S, Dhe-Paganon S | display-authors = 6 | title = Structure of LIMP-2 provides functional insights with implications for SR-BI and CD36 | journal = Nature | volume = 504 | issue = 7478 | pages = 172–6 | date = December 2013 | pmid = 24162852 | doi = 10.1038/nature12684 | bibcode = 2013Natur.504..172N | s2cid = 4395239 }}</ref> Like SCARB2, CD36 is proposed to contain an [[antiparallel (biochemistry)#Beta sheet|antiparallel]] β-barrel core with many short α-helices adorning it. The structure is predicted to contain a hydrophobic transport tunnel. 
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]].<ref name="pmid9371725">{{cite journal | vauthors = 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 = The Biochemical Journal | volume = 328 | issue = 2 | pages = 635–42 | date = December 1997 | pmid = 9371725 | pmc = 1218965 | doi = 10.1042/bj3280635 }}</ref> 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 [[post-translational modification]]s have been reported for CD36. CD36 is modified with 4 [[palmitoyl chains]], 2 on each of the two intracellular domains.<ref name="pmid8798390"/> 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.<ref name="pmid12947091">{{cite journal | vauthors = 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 = The Journal of Biological Chemistry | volume = 278 | issue = 46 | pages = 45931–6 | date = November 2003 | pmid = 12947091 | doi = 10.1074/jbc.M307722200 | doi-access = free }}</ref><ref name="pmid15496455">{{cite journal | vauthors = 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 = Molecular Biology of the Cell | volume = 16 | issue = 1 | pages = 24–31 | date = January 2005 | pmid = 15496455 | pmc = 539148 | doi = 10.1091/mbc.E04-07-0616 }}</ref> CD36 could be also phosphorylated at Y62, T92, T323,<ref name="urlwww.phosphosite.org">{{cite web | url = http://www.phosphosite.org/proteinAction.do?id=18224&showAllSites=true | title = CD36 (human) protein page |vauthors=Hornbeck PV, Kornhauser JM, Tkachev S, Zhang B, Skrzypek E, Murray B, Latham V, Sullivan M | work = PhosphoSitePlus | publisher = Cell Signaling Technology, Inc. }}</ref> ubiquitinated at K56, K469, K472 and acetylated at K52, K56, K166, K231, K394, K398, K403.<ref name="pmid18353783">{{cite journal | vauthors = Smith J, Su X, El-Maghrabi R, Stahl PD, Abumrad NA | title = Opposite regulation of CD36 ubiquitination by fatty acids and insulin: effects on fatty acid uptake | journal = The Journal of Biological Chemistry | volume = 283 | issue = 20 | pages = 13578–85 | date = May 2008 | pmid = 18353783 | pmc = 2376227 | doi = 10.1074/jbc.M800008200 | doi-access = free }}</ref><ref name="pmid23603908">{{cite journal | vauthors = Kuda O, Pietka TA, Demianova Z, Kudova E, Cvacka J, Kopecky J, Abumrad NA | title = Sulfo-N-succinimidyl oleate (SSO) inhibits fatty acid uptake and signaling for intracellular calcium via binding CD36 lysine 164: SSO also inhibits oxidized low density lipoprotein uptake by macrophages | journal = The Journal of Biological Chemistry | volume = 288 | issue = 22 | pages = 15547–55 | date = May 2013 | pmid = 23603908 | pmc = 3668716 | doi = 10.1074/jbc.M113.473298 | doi-access = free }}</ref><ref name="pmid22902405">{{cite journal | vauthors = Lundby A, Lage K, Weinert BT, Bekker-Jensen DB, Secher A, Skovgaard T, Kelstrup CD, Dmytriyev A, Choudhary C, Lundby C, Olsen JV | display-authors = 6 | title = Proteomic analysis of lysine acetylation sites in rat tissues reveals organ specificity and subcellular patterns | journal = Cell Reports | volume = 2 | issue = 2 | pages = 419–31 | date = August 2012 | pmid = 22902405 | pmc = 4103158 | doi = 10.1016/j.celrep.2012.07.006 }}</ref>

=== 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]].<ref name="pmid9268192">{{cite journal | vauthors = Daviet L, Malvoisin E, Wild TF, McGregor JL | title = Thrombospondin induces dimerization of membrane-bound, but not soluble CD36 | journal = Thrombosis and Haemostasis | volume = 78 | issue = 2 | pages = 897–901 | date = August 1997 | pmid = 9268192 | doi = 10.1055/s-0038-1657649 | s2cid = 43232897 }}</ref>

== Genetics ==

In humans, the [[gene]] is located on the long arm of [[chromosome 7]] at band 11.2 (7q11.2<ref name="pmid7503937">{{cite journal | vauthors = 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 | date = September 1993 | pmid = 7503937 | doi = 10.1006/geno.1993.1401 | hdl = 2436/7706 | hdl-access = free }}</ref>) 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 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 [[medication|drugs]] and the [[vitamin A]] metabolite 9-cis-[[retinoic acid]] respectively.

== Tissue distribution ==

CD36 is found on [[platelet]]s, [[erythrocyte]]s, [[monocyte]]s, differentiated [[adipocyte]]s, skeletal muscle, [[mammary epithelial cell]]s, [[spleen]] cells and some [[skin]] microdermal [[endothelial cell]]s.

== Function ==

The protein itself belongs to the class B [[scavenger receptor (immunology)|scavenger receptor]] family which includes receptors for selective cholesteryl ester uptake, [[SCARB1|scavenger receptor class B type I]] (SR-BI) and [[SCARB2|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.<ref>{{cite journal | vauthors = Armesilla AL, Vega MA | title = Structural organization of the gene for human CD36 glycoprotein | journal = The Journal of Biological Chemistry | volume = 269 | issue = 29 | pages = 18985–91 | date = July 1994 | doi = 10.1016/S0021-9258(17)32263-9 | pmid = 7518447 | doi-access = free | hdl = 2436/7744 | hdl-access = free }}</ref>

On [[macrophages]] CD36 forms part of a [[non-opsonic receptor]] (the scavenger receptor CD36/[[alpha-v beta-3]] complex) and is involved in [[phagocytosis]].<ref>{{cite journal | vauthors = Erdman LK, Cosio G, Helmers AJ, Gowda DC, Grinstein S, Kain KC | title = CD36 and TLR interactions in inflammation and phagocytosis: implications for malaria | journal = Journal of Immunology | volume = 183 | issue = 10 | pages = 6452–9 | date = November 2009 | pmid = 19864601 | pmc = 2853812 | doi = 10.4049/jimmunol.0901374 }}</ref>

CD36 has also been implicated in [[hemostasis]], [[thrombosis]], [[malaria]], [[inflammation]], [[lipid]] [[metabolism]] and [[atherogenesis]].<ref>{{cite journal | vauthors = Daviet L, McGregor JL | title = Vascular biology of CD36: roles of this new adhesion molecule family in different disease states | journal = Thrombosis and Haemostasis | volume = 78 | issue = 1 | pages = 65–9 | date = July 1997 | pmid = 9198129 | doi = 10.1055/s-0038-1657502 | s2cid = 21113427 }}</ref>

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.<ref name="pmid19740737">{{cite journal | vauthors = Collins RF, Touret N, Kuwata H, Tandon NN, Grinstein S, Trimble WS | title = Uptake of oxidized low density lipoprotein by CD36 occurs by an actin-dependent pathway distinct from macropinocytosis | journal = The Journal of Biological Chemistry | volume = 284 | issue = 44 | pages = 30288–97 | date = October 2009 | pmid = 19740737 | pmc = 2781584 | doi = 10.1074/jbc.M109.045104 | doi-access = free }}</ref> Unlike macropinocytosis this process is not affected by [[PI3K inhibitor|inhibitors of phosphatidylinositol 3-kinase]] or Na<sup>+</sup>/H<sup>+</sup> exchange.

CD36 ligands have also been shown to promote sterile inflammation through assembly of a [[Toll-like receptor]] 4 and 6 heterodimer.<ref name="pmid20037584">{{cite journal | vauthors = Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, Rayner KJ, Boyer L, Zhong R, Frazier WA, Lacy-Hulbert A, El Khoury J, Golenbock DT, Moore KJ | display-authors = 6 | title = CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer | journal = Nature Immunology | volume = 11 | issue = 2 | pages = 155–61 | date = February 2010 | pmid = 20037584 | pmc = 2809046 | doi = 10.1038/ni.1836 }}</ref>

Recently, CD36 was linked to store-operated calcium flux, [[Phospholipase A2|phospholipase A<sub>2</sub>]] activation, and production of [[prostaglandin E2|prostaglandin E<sub>2</sub>]]<ref name="pmid21454644">{{cite journal | vauthors = Kuda O, Jenkins CM, Skinner JR, Moon SH, Su X, Gross RW, Abumrad NA | title = CD36 protein is involved in store-operated calcium flux, phospholipase A2 activation, and production of prostaglandin E2 | journal = The Journal of Biological Chemistry | volume = 286 | issue = 20 | pages = 17785–95 | date = May 2011 | pmid = 21454644 | pmc = 3093854 | doi = 10.1074/jbc.M111.232975 | doi-access = free }}</ref>

CD36 function in long-chain fatty acid uptake and signaling can be irreversibly inhibited by [[sulfo-N-succinimidyl oleate]] (SSO), which binds lysine 164 within a hydrophobic pocket shared by several CD36 ligands, e.g. fatty acid and oxLDL.<ref name="pmid23603908"/> Recent research concluded that CD36 is involved in the fat taste transduction ([[oleogustus]]).

== 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 adhere 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 [[Plasmodium falciparum erythrocyte membrane protein 1|''Plasmodium falciparum'' 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 [[promoter (biology)|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="pmid17339496">{{cite journal | vauthors = 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 = Journal of Immunology | volume = 178 | issue = 6 | pages = 3954–61 | date = March 2007 | pmid = 17339496 | doi = 10.4049/jimmunol.178.6.3954 | doi-access = free }}</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 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 [[Africa]]n (2.5%), [[Japan]]ese, and other [[Asia]]n populations (5-11%).

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.<ref name="pmid2617957">{{cite journal | vauthors = Ikeda H, Mitani T, Ohnuma M, Haga H, Ohtzuka S, Kato T, Nakase T, Sekiguchi S | display-authors = 6 | title = A new platelet-specific antigen, Naka, involved in the refractoriness of HLA-matched platelet transfusion | journal = Vox Sanguinis | volume = 57 | issue = 3 | pages = 213–7 | year = 1989 | pmid = 2617957 | doi = 10.1111/j.1423-0410.1989.tb00826.x  |doi-access=free | s2cid = 39521299 }}</ref><ref name="pmid1699620">{{cite journal | vauthors = Yamamoto N, Ikeda H, Tandon NN, Herman J, Tomiyama Y, Mitani T, Sekiguchi S, Lipsky R, Kralisz U, Jamieson GA | display-authors = 6 | 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 | date = November 1990 | pmid = 1699620 | doi = 10.1182/blood.V76.9.1698.1698 | url = http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=1699620 | doi-access = free | url-access = subscription }}</ref> 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]].<ref name="pmid1707534">{{cite journal | vauthors = 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 = Proceedings of the National Academy of Sciences of the United States of America | volume = 88 | issue = 8 | pages = 3175–9 | date = April 1991 | pmid = 1707534 | pmc = 51408 | doi = 10.1073/pnas.88.8.3175 | bibcode = 1991PNAS...88.3175O | doi-access = free }}</ref>

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 erythroblasts the phenotype is classified as type 2b.<ref name="pmid11602321">{{cite journal | vauthors = Toba K, Hanawa H, Watanabe K, Fuse I, Masuko M, Miyajima S, Takahashi M, Sakaue M, Abo T, Aizawa Y | display-authors = 6 | title = Erythroid involvement in CD36 deficiency | journal = Experimental Hematology | volume = 29 | issue = 10 | pages = 1194–200 | date = October 2001 | pmid = 11602321 | doi = 10.1016/S0301-472X(01)00691-9 | doi-access = free }}</ref> 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.

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.<ref name="pmid11019968">{{cite journal | vauthors = Yanai H, Chiba H, Fujiwara H, Morimoto M, Abe K, Yoshida S, Takahashi Y, Fuda H, Hui SP, Akita H, Kobayashi K, Matsuno K | display-authors = 6 | title = Phenotype-genotype correlation in CD36 deficiency types I and II | journal = Thrombosis and Haemostasis | volume = 84 | issue = 3 | pages = 436–41 | date = September 2000 | pmid = 11019968 | doi = 10.1055/s-0037-1614041 | s2cid = 42193140 }}</ref> In 1127 healthy French blood donors (almost all of whom were white Europeans) no CD36 deficiency was found.<ref name="pmid10504124">{{cite journal | vauthors = Lee K, Godeau B, Fromont P, Plonquet A, Debili N, Bachir D, Reviron D, Gourin J, Fernandez E, Galactéros F, Bierling P | display-authors = 6 | title = CD36 deficiency is frequent and can cause platelet immunization in Africans | journal = Transfusion | volume = 39 | issue = 8 | pages = 873–9 | date = August 1999 | pmid = 10504124 | doi = 10.1046/j.1537-2995.1999.39080873.x | s2cid = 21921171 | doi-access = free }}</ref> 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.<ref name="pmid8623134">{{cite journal | vauthors = 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 | date = April 1996 | pmid = 8623134 | doi = 10.1046/j.1537-2995.1996.36496226147.x | s2cid = 10991605 }}</ref>

CD36 deficiency may be a cause of post transfusion [[purpura]].<ref name="pmid7570941">{{cite journal | vauthors = Bierling P, Godeau B, Fromont P, Bettaieb A, Debili N, el-Kassar N, Rouby JJ, Vainchenker W, Duedari N | display-authors = 6 | title = Posttransfusion purpura-like syndrome associated with CD36 (Naka) isoimmunization | journal = Transfusion | volume = 35 | issue = 9 | pages = 777–82 | date = September 1995 | pmid = 7570941 | doi = 10.1046/j.1537-2995.1995.35996029165.x | s2cid = 22706156 }}</ref>

=== Blood pressure ===
Below normal levels of CD36 expression in the kidneys has been implicated as a genetic risk factor for [[hypertension]] (high blood pressure).<ref name="pmid18587397">{{cite journal | vauthors = 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 | display-authors = 6 | title = Identification of renal Cd36 as a determinant of blood pressure and risk for hypertension | journal = Nature Genetics | volume = 40 | issue = 8 | pages = 952–4 | date = August 2008 | pmid = 18587397 | doi = 10.1038/ng.164 | s2cid = 6857655 }}</ref>

=== Fatty acid uptake ===

An association with myocardial fatty acid uptake in humans has been noted.<ref name="pmid9707006">{{cite journal | vauthors = 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 = Japanese Circulation Journal | volume = 62 | issue = 7 | pages = 499–504 | date = July 1998 | pmid = 9707006 | doi = 10.1253/jcj.62.499 | doi-access = free }}</ref> The data suggest a link between [[hypertrophic cardiomyopathy]] and CD36 but this needs to be confirmed.

=== Tuberculosis ===

[[RNAi]] screening in a ''[[Drosophila]]'' model has revealed that a member of the CD36 family is required for [[phagocytosis]] of ''[[Mycobacterium tuberculosis]]'' into macrophage phagosomes.<ref name="pmid16020694">{{cite journal | vauthors = Philips JA, Rubin EJ, Perrimon N | s2cid = 26751583 | title = Drosophila RNAi screen reveals CD36 family member required for mycobacterial infection | journal = Science | volume = 309 | issue = 5738 | pages = 1251–3 | date = August 2005 | pmid = 16020694 | doi = 10.1126/science.1116006 | bibcode = 2005Sci...309.1251P | doi-access = free }}</ref>

=== Toxoplasmosis ===

Avirulent strains of ''[[Toxoplasma gondii]]'' bind to CD36 but virulent parasites fail to engage CD36. In mice, CD36 is required for disease tolerance but not for the development of immunity or resistance.<ref name="pmid34400524">{{cite journal | vauthors = Zhao Y, Reyes, J, Rovira-Diaz E, Fox BA, Bzik D, Yap GS | title = CD36 mediates phagocyte tropism and avirulence of Toxoplasma gondii | journal = Journal of Immunology |date = August 2021 | volume = 207 | issue = 6 | pages = 1507–1512 | pmid = 34400524 | doi = 10.4049/jimmunol.2100605 | issn=0022-1767 | pmc = 8429199 | s2cid = 237148810 }}</ref>

=== Obesity ===

CD36's association with the ability to [[taste]] fats has made it a target for various studies regarding [[obesity]] and alteration of [[lipid]] [[taste|tasting]]. CD36 mRNA expression was found to be reduced in [[taste bud]] cells (TBC) of obese [[sand rat]]s (''P. obesus'') compared to lean controls, implicating an association between CD36 and obesity.<ref name="Abdoul-Azize S, Atek-Mebarki F, Bitam A, Sadou H, Koceïr EA, Khan NA 2013 e68532">{{cite journal | vauthors = Abdoul-Azize S, Atek-Mebarki F, Bitam A, Sadou H, Koceïr EA, Khan NA | title = Oro-gustatory perception of dietary lipids and calcium signaling in taste bud cells are altered in nutritionally obesity-prone Psammomys obesus | journal = PLOS ONE | volume = 8 | issue = 8 | pages = e68532 | year = 2013 | pmid = 23936306 | pmc = 3731325 | doi = 10.1371/journal.pone.0068532 | bibcode = 2013PLoSO...868532A | doi-access = free }}</ref> Although actual levels of CD36 protein were not different between the obese and control rat cells, Abdoul-Azize et al. hypothesize that the physical distribution of CD36 could differ in obese rat cells.<ref name="Abdoul-Azize S, Atek-Mebarki F, Bitam A, Sadou H, Koceïr EA, Khan NA 2013 e68532"/> Changes in calcium mediation have been associated with CD36 and obesity as well. Taste bud cells (more specifically, cells from the [[lingual papilla|circumvallate papillae]]) containing CD36 that were isolated from obese mice exhibited a significantly smaller increase in calcium after fatty acid stimulation when compared to control mice:<ref name="Chevrot M, Bernard A, Ancel D, Buttet M, Martin C, Abdoul-Azize S, Merlin JF, Poirier H, Niot I, Khan NA, Passilly-Degrace P, Besnard P 2013 2485–94">{{cite journal | vauthors = Chevrot M, Bernard A, Ancel D, Buttet M, Martin C, Abdoul-Azize S, Merlin JF, Poirier H, Niot I, Khan NA, Passilly-Degrace P, Besnard P | display-authors = 6 | title = Obesity alters the gustatory perception of lipids in the mouse: plausible involvement of lingual CD36 | journal = Journal of Lipid Research | volume = 54 | issue = 9 | pages = 2485–94 | date = September 2013 | pmid = 23840049 | pmc = 3735945 | doi = 10.1194/jlr.M039446  |doi-access=free }}</ref> CD36 associated calcium regulation is impaired when mice are made to be obese (but not in normal weight mice), and this could be a mechanism contributing to behavior changes in the obese mice, such as decreased lipid taste sensitivity and decreased attraction to fats.<ref name="Chevrot M, Bernard A, Ancel D, Buttet M, Martin C, Abdoul-Azize S, Merlin JF, Poirier H, Niot I, Khan NA, Passilly-Degrace P, Besnard P 2013 2485–94"/>

There has been some investigation into human CD36 as well. A study examined oral detection of fat in obese subjects with genetic bases for high, medium, and low expression of the CD36 receptor. Those subjects with high CD36 expression were eight times more sensitive to certain fats ([[oleic acid]] and [[triolein]]) than the subjects with low CD36 expression.<ref name="Pepino_2012"/> Those subjects with an intermediate amount of CD36 expression were sensitive to fat at a level between the high and low groups.<ref name="Pepino_2012"/> This study demonstrates that there is a significant relationship between oral fat sensitivity and the amount of CD36 receptor expression, but further investigation into CD36 could be useful for learning more about lipid tasting in the context of obesity, as CD36 may be a target for therapies in the future.

=== Establishment of cellular senescence ===

Reducing the burden of senescent cells, or reducing their inflammatory secretome through CD36 neutralization, accelerates regeneration in young and old mice.<ref>{{cite journal | vauthors = Moiseeva V | display-authors = etal | year = 2022 | title = Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration | journal = Nature | volume = 612| issue = 7941| pages = 169–178 | doi = 10.1038/s41586-022-05535-x | pmid = 36544018| pmc = 9812788}}{{Creative Commons text attribution notice|cc=by3|from this source=yes}}</ref>

==Cancer==

CD36 plays a role in the regulation of [[angiogenesis]], which may be a therapeutic strategy for controlling the spread of cancer.<ref name="pmid15790550">{{cite journal | vauthors = Ge Y, Elghetany MT | title = CD36: a multiligand molecule | journal = Laboratory Hematology | volume = 11 | issue = 1 | pages = 31–7 | year = 2005 | pmid = 15790550 | doi = 10.1532/LH96.04056 }}</ref> Some data from ''in vitro'' and animal studies suggested that fatty acid uptake through CD36 may promote cancer cell migration and proliferation in hepatocellular carcinoma, [[glioblastoma]], and potentially other cancers; there was limited data from observational studies in people that low CD36 may correlate with a slightly better outcome in glioblastoma.<ref name="pmid26938658">{{cite journal | vauthors = Selwan EM, Finicle BT, Kim SM, Edinger AL | title = Attacking the supply wagons to starve cancer cells to death | journal = FEBS Letters | volume = 590 | issue = 7 | pages = 885–907 | date = April 2016 | pmid = 26938658 | pmc = 4833639 | doi = 10.1002/1873-3468.12121 }}</ref>

== Interactions ==

CD36 has been shown to [[Protein-protein interaction|interact]] with [[FYN]].<ref name="pmid1715582">{{cite journal | vauthors = Huang MM, Bolen JB, Barnwell JW, Shattil SJ, Brugge JS | title = Membrane glycoprotein IV (CD36) is physically associated with the Fyn, Lyn, and Yes protein-tyrosine kinases in human platelets | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 88 | issue = 17 | pages = 7844–8 | date = September 1991 | pmid = 1715582 | pmc = 52400 | doi = 10.1073/pnas.88.17.7844 | bibcode = 1991PNAS...88.7844H | doi-access = free }}</ref><ref name="pmid7521304">{{cite journal | vauthors = Bull HA, Brickell PM, Dowd PM | title = Src-related protein tyrosine kinases are physically associated with the surface antigen CD36 in human dermal microvascular endothelial cells | journal = FEBS Letters | volume = 351 | issue = 1 | pages = 41–4 | date = August 1994 | pmid = 7521304 | doi = 10.1016/0014-5793(94)00814-0 | s2cid = 45071719 | doi-access =  }}</ref>

==Related proteins==
{{Infobox protein family 
| Symbol = CD36 
| Name = CD36 family 
| image = 4f7b_1.png
| width = 
| caption = Structure of Limp-II. PDB entry {{PDBe|4f7b}}
| Pfam= PF01130
| InterPro= IPR002159
| SMART= 
| Prosite = 
| SCOP = 
| TCDB = 
| OPM family= 
| OPM protein= 
| PDB= 
}} 
Other human [[scavenger receptor (immunology)|scavenger receptor]]s related to CD36 are [[SCARB1]] and [[SCARB2]] proteins.

== See also ==
* [[Cluster of differentiation]]
* [[CD36 antigen]]
{{Clear}}

== References ==
{{Reflist|2}}

== Further reading ==
{{Refbegin}}
* {{cite journal | vauthors = Ren H, Han R, Chen X, Liu X, Wan J, Wang L, Yang X, Wang J | title = Potential therapeutic targets for intracerebral hemorrhage-associated inflammation: An update | journal = J Cereb Blood Flow Metab | date = May 2020 | volume = 40 | issue = 9 | pages = 1752–1768 | pmid = 32423330 | doi = 10.1177/0271678X20923551| pmc = 7446569 }}
* {{cite journal | vauthors = Febbraio M, Silverstein RL | title = CD36: implications in cardiovascular disease | journal = The International Journal of Biochemistry & Cell Biology | volume = 39 | issue = 11 | pages = 2012–30 | year = 2007 | pmid = 17466567 | pmc = 2034445 | doi = 10.1016/j.biocel.2007.03.012 }}
* {{cite journal | vauthors = Abumrad NA, Ajmal M, Pothakos K, Robinson JK | title = CD36 expression and brain function: does CD36 deficiency impact learning ability? | journal = Prostaglandins & Other Lipid Mediators | volume = 77 | issue = 1–4 | pages = 77–83 | date = September 2005 | pmid = 16099393 | doi = 10.1016/j.prostaglandins.2004.09.012 }}
* {{cite web | url = http://www.sciam.com/article.cfm?chanID=sa003&articleID=000AFE88-E770-1367-A6B083414B7F4945 | title = Potential Taste Receptor for Fat Identified | vauthors = Biello D | date = 2005-11-02 | publisher = Scientific American | archive-url = https://web.archive.org/web/20070926222808/http://www.sciam.com/article.cfm?chanID=sa003&articleID=000AFE88-E770-1367-A6B083414B7F4945 | archive-date = 2007-09-26 | access-date = 2008-08-05 | url-status = dead }}
{{Refend}}

== External links ==
* {{UCSC gene info|CD36}}

{{Clusters of differentiation}}

{{DEFAULTSORT:Cd36}}
[[Category:Clusters of differentiation]]
[[Category:Membrane proteins]]
[[Category:Receptors]]
[[Category:Scavenger receptors]]