# CD36

## Overview
CD36 is a gene that encodes the CD36 molecule, a multifunctional transmembrane glycoprotein widely expressed in various tissues, including adipose tissue, muscle, and macrophages. The CD36 protein functions primarily as a receptor involved in the uptake of fatty acids and the clearance of oxidized low-density lipoproteins, playing a critical role in lipid metabolism and immune system regulation. Structurally, CD36 features two transmembrane domains, two cytoplasmic tails, and a heavily glycosylated extracellular domain, which is essential for its interaction with multiple ligands and participation in diverse biological processes such as angiogenesis, inflammation, and atherogenesis (Chu2012CD36; Pepino2014Structure-Function). The gene's expression and the protein's activity are implicated in various metabolic and cardiovascular diseases, highlighting its importance in health and disease (Love-Gregory2008Variants; Masuda2015Diverse).

## Structure
The CD36 protein is a transmembrane glycoprotein encoded by the CD36 gene, characterized by a complex molecular structure that supports its multifunctional roles. The protein comprises two transmembrane domains and two cytoplasmic tails, with a large extracellular domain that is highly glycosylated (rac2007molecular). This extracellular domain contains three disulfide bridges crucial for its structural integrity and function (Pepino2014Structure-Function).

CD36's molecular architecture includes a central hydrophobic cavity that spans most of its length, accommodating fatty acids such as palmitic and stearic acids. This cavity is lined predominantly by hydrophobic side chains, facilitating lipid transport (Hsieh2016The). The protein also features a hairpin-like membrane topology, which is significant for its interactions with various ligands, including fatty acids and oxidized low-density lipoproteins (Pepino2014Structure-Function).

Post-translational modifications of CD36 are diverse, including phosphorylation, glycosylation, palmitoylation, ubiquitination, and acetylation, which are essential for modulating its trafficking, ligand uptake, and signal transduction functions (Pepino2014Structure-Function). Additionally, alternative splicing of CD36 pre-mRNA can lead to isoforms with variations in structure and function, such as those lacking specific amino acids and glycosylation sites due to exon skipping (rac2007molecular).

Overall, the structural features and modifications of CD36 are integral to its role as a receptor involved in lipid metabolism and immune responses.

## Function
CD36, a multifunctional glycoprotein, is primarily recognized as a scavenger receptor involved in lipid metabolism and immune regulation. It facilitates the uptake of long-chain fatty acids into tissues such as muscle and adipose, which is crucial for energy storage and metabolism (Andersen2006Alternative). CD36 also plays a significant role in the clearance of oxidized low-density lipoproteins (oxLDL) by macrophages, a process integral to the development of atherosclerotic plaques (Maruyama2008Nrf2; Vallvé2002Unsaturated).

In cell biology, CD36 functions as a receptor for thrombospondin and collagen, mediating cellular adhesion and signaling pathways that influence cell structure and function (Tang1994Identification; rac2007molecular). This protein is also involved in the cytoadherence of erythrocytes infected with Plasmodium falciparum, contributing to the pathology of malaria (Tang1994Identification).

Furthermore, CD36 is implicated in the immune system, particularly in the recognition and ingestion of apoptotic cells by macrophages and dendritic cells, which is essential for maintaining immune homeostasis and preventing autoimmunity (Urban2001A). The protein's role extends to modulating inflammation and angiogenesis, linking it to broader physiological and pathological processes (Andersen2006Alternative).

## Clinical Significance
Mutations in the CD36 gene and alterations in its expression levels are linked to a variety of metabolic and cardiovascular diseases. CD36 deficiency, resulting from genetic mutations such as C268T and 949insA, can lead to abnormalities in myocardial uptake of long-chain fatty acids, contributing to conditions like hereditary hypertrophic cardiomyopathy (Masuda2015Diverse). This deficiency is also associated with altered lipid profiles, potentially leading to high plasma triglycerides and low HDL levels, and impairing glucose metabolism which may result in insulin resistance (Masuda2015Diverse).

Increased expression of CD36 has been observed in diabetic cardiomyopathy and atherosclerosis, while decreased expression is noted in pathological cardiac hypertrophy due to ischemia-reperfusion and pressure overload (Shu2020The). Specific single nucleotide polymorphisms (SNPs) in the CD36 gene, such as rs1761667 and rs1049673, are associated with an increased risk of coronary heart disease and extreme lipid profiles (Shu2020The).

Furthermore, CD36 interacts with nuclear receptors like PPAR and RORa, which are involved in lipid metabolism and regulation of HDL-C, highlighting its role in metabolic syndrome and cardiovascular health (Love-Gregory2008Variants). Variants in CD36 also influence susceptibility to type 2 diabetes and cardiovascular disease, underscoring the gene's significant impact on metabolic and cardiovascular disorders (Love-Gregory2008Variants).

## Interactions
CD36 interacts with a variety of proteins and ligands, mediating crucial cellular functions. It serves as a receptor for thrombospondin-1 (TSP-1), with specific interactions occurring through its CLESH domain. Phosphorylation of this domain can inhibit its binding capacity, highlighting a regulatory mechanism influenced by protein kinase C (Chu2012CD36). Additionally, CD36 binds to the insulin receptor (IR) in human myotubes, enhancing insulin signaling by facilitating the tyrosine phosphorylation of IR, which is mediated by the recruitment of the Src family kinase Fyn (Yang2020Loss).

In the context of immune responses, CD36 interacts with Toll-like receptors (TLRs), particularly TLR2 and TLR6, playing a role in the innate immune response to bacterial pathogens (Zingg2017α‐Tocopheryl). It also binds various forms of oxidized low-density lipoproteins (oxLDL) and facilitates their uptake, a process significant in the development of atherosclerosis (Banesh2022Hemin).

Furthermore, CD36 is involved in malaria pathology by binding to the CIDRa domains of PfEMP1 proteins from Plasmodium falciparum, which helps the parasite evade immune clearance by adhering to endothelial receptors (Hsieh2016The). This interaction involves a conserved hydrophobic pocket on CD36 that accommodates a phenylalanine residue from the CIDRa domains, crucial for the binding specificity and strength (Hsieh2016The).


## References


[1. (Tang1994Identification) Y. Tang, K.T. Taylor, D.A. Sobieski, E.S. Medved, and R.H. Lipsky. Identification of a human cd36 isoform produced by exon skipping. conservation of exon organization and pre-mrna splicing patterns with a cd36 gene family member, cla-1. Journal of Biological Chemistry, 269(8):6011–6015, February 1994. URL: http://dx.doi.org/10.1016/s0021-9258(17)37562-2, doi:10.1016/s0021-9258(17)37562-2. (53 citations) 10.1016/s0021-9258(17)37562-2](https://doi.org/10.1016/s0021-9258(17)37562-2)

[2. (Zingg2017α‐Tocopheryl) Jean‐Marc Zingg, Angelo Azzi, and Mohsen Meydani. Α‐tocopheryl phosphate induces vegf expression via cd36/pi3kγ in thp‐1 monocytes. Journal of Cellular Biochemistry, 118(7):1855–1867, March 2017. URL: http://dx.doi.org/10.1002/jcb.25871, doi:10.1002/jcb.25871. (14 citations) 10.1002/jcb.25871](https://doi.org/10.1002/jcb.25871)

[3. (Banesh2022Hemin) Sooram Banesh, Sourav Layek, and Vishal Trivedi. Hemin acts as cd36 ligand to activate down-stream signalling to disturb immune responses and cytokine secretion from macrophages. Immunology Letters, 243:1–18, March 2022. URL: http://dx.doi.org/10.1016/j.imlet.2022.01.004, doi:10.1016/j.imlet.2022.01.004. (8 citations) 10.1016/j.imlet.2022.01.004](https://doi.org/10.1016/j.imlet.2022.01.004)

[4. (Vallvé2002Unsaturated) Joan-Carles Vallvé, Katia Uliaque, Josefa Girona, Anna Cabré, Josep Ribalta, Mercedes Heras, and Lluı́s Masana. Unsaturated fatty acids and their oxidation products stimulate cd36 gene expression in human macrophages. Atherosclerosis, 164(1):45–56, September 2002. URL: http://dx.doi.org/10.1016/s0021-9150(02)00046-1, doi:10.1016/s0021-9150(02)00046-1. (95 citations) 10.1016/s0021-9150(02)00046-1](https://doi.org/10.1016/s0021-9150(02)00046-1)

[5. (Shu2020The) Hongyang Shu, Yizhong Peng, Weijian Hang, Jiali Nie, Ning Zhou, and Dao Wen Wang. The role of cd36 in cardiovascular disease. Cardiovascular Research, 118(1):115–129, November 2020. URL: http://dx.doi.org/10.1093/cvr/cvaa319, doi:10.1093/cvr/cvaa319. (79 citations) 10.1093/cvr/cvaa319](https://doi.org/10.1093/cvr/cvaa319)

[6. (Masuda2015Diverse) Yuya Masuda, Shogo Tamura, Kazuhiko Matsuno, Ayumi Nagasawa, Koji Hayasaka, Chikara Shimizu, and Takanori Moriyama. Diverse cd36 expression among japanese population: defective cd36 mutations cause platelet and monocyte cd36 reductions in not only deficient but also normal phenotype subjects. Thrombosis Research, 135(5):951–957, May 2015. URL: http://dx.doi.org/10.1016/j.thromres.2015.03.002, doi:10.1016/j.thromres.2015.03.002. (23 citations) 10.1016/j.thromres.2015.03.002](https://doi.org/10.1016/j.thromres.2015.03.002)

[7. (Hsieh2016The) Fu-Lien Hsieh, Louise Turner, Jani Reddy Bolla, Carol V. Robinson, Thomas Lavstsen, and Matthew K. Higgins. The structural basis for cd36 binding by the malaria parasite. Nature Communications, September 2016. URL: http://dx.doi.org/10.1038/ncomms12837, doi:10.1038/ncomms12837. (210 citations) 10.1038/ncomms12837](https://doi.org/10.1038/ncomms12837)

[8. (Andersen2006Alternative) Malin Andersen, Boris Lenhard, Carl Whatling, Per Eriksson, and Jacob Odeberg. Alternative promoter usage of the membrane glycoprotein cd36. BMC Molecular Biology, March 2006. URL: http://dx.doi.org/10.1186/1471-2199-7-8, doi:10.1186/1471-2199-7-8. (45 citations) 10.1186/1471-2199-7-8](https://doi.org/10.1186/1471-2199-7-8)

[9. (Yang2020Loss) Ping Yang, Han Zeng, Wei Tan, Xiaoqing Luo, Enze Zheng, Lei Zhao, Li Wei, Xiong Z. Ruan, Yao Chen, and Yaxi Chen. Loss of cd36 impairs hepatic insulin signaling by enhancing the interaction of ptp1b with ir. The FASEB Journal, 34(4):5658–5672, February 2020. URL: http://dx.doi.org/10.1096/fj.201902777RR, doi:10.1096/fj.201902777rr. (22 citations) 10.1096/fj.201902777RR](https://doi.org/10.1096/fj.201902777RR)

[10. (Chu2012CD36) Ling-Yun Chu and Roy L. Silverstein. Cd36 ectodomain phosphorylation blocks thrombospondin-1 binding: structure-function relationships and regulation by protein kinase c. Arteriosclerosis, Thrombosis, and Vascular Biology, 32(3):760–767, March 2012. URL: http://dx.doi.org/10.1161/atvbaha.111.242511, doi:10.1161/atvbaha.111.242511. (44 citations) 10.1161/atvbaha.111.242511](https://doi.org/10.1161/atvbaha.111.242511)

[11. (Urban2001A) Britta C. Urban, Nick Willcox, and David J. Roberts. A role for cd36 in the regulation of dendritic cell function. Proceedings of the National Academy of Sciences, 98(15):8750–8755, July 2001. URL: http://dx.doi.org/10.1073/pnas.151028698, doi:10.1073/pnas.151028698. (377 citations) 10.1073/pnas.151028698](https://doi.org/10.1073/pnas.151028698)

[12. (rac2007molecular) Rać, Monika Ewa, Krzysztof Safranow, and Wojciech Poncyljusz. "Molecular basis of human CD36 gene mutations." Molecular Medicine 13 (2007): 288-296. (192 citations) 10.2119/2006-00088](https://doi.org/10.2119/2006-00088)

[13. (Maruyama2008Nrf2) Atsushi Maruyama, Saho Tsukamoto, Keizo Nishikawa, Aruto Yoshida, Nobuhiko Harada, Kiyoto Motojima, Tetsuro Ishii, Akio Nakane, Masayuki Yamamoto, and Ken Itoh. Nrf2 regulates the alternative first exons of cd36 in macrophages through specific antioxidant response elements. Archives of Biochemistry and Biophysics, 477(1):139–145, September 2008. URL: http://dx.doi.org/10.1016/j.abb.2008.06.004, doi:10.1016/j.abb.2008.06.004. (82 citations) 10.1016/j.abb.2008.06.004](https://doi.org/10.1016/j.abb.2008.06.004)

[14. (Love-Gregory2008Variants) Latisha Love-Gregory, Richard Sherva, Lingwei Sun, Jon Wasson, Timothy Schappe, Alessandro Doria, D.C. Rao, Steven C. Hunt, Samuel Klein, Rosalind J. Neuman, M. Alan Permutt, and Nada A. Abumrad. Variants in the cd36 gene associate with the metabolic syndrome and high-density lipoprotein cholesterol. Human Molecular Genetics, 17(11):1695–1704, February 2008. URL: http://dx.doi.org/10.1093/hmg/ddn060, doi:10.1093/hmg/ddn060. (229 citations) 10.1093/hmg/ddn060](https://doi.org/10.1093/hmg/ddn060)

[15. (Pepino2014Structure-Function) Marta Yanina Pepino, Ondrej Kuda, Dmitri Samovski, and Nada A. Abumrad. Structure-function of cd36 and importance of fatty acid signal transduction in fat metabolism. Annual Review of Nutrition, 34(1):281–303, July 2014. URL: http://dx.doi.org/10.1146/annurev-nutr-071812-161220, doi:10.1146/annurev-nutr-071812-161220. (564 citations) 10.1146/annurev-nutr-071812-161220](https://doi.org/10.1146/annurev-nutr-071812-161220)