CD36 - CD36 molecule |Elisa - Clia - Antibody - Protein

Background

CD36, also known as platelet glycoprotein IV (GPIV) or fatty acid translocase (FAT), is a multifunctional membrane glycoprotein involved in various physiological processes, including lipid metabolism, immune response, angiogenesis, and pathogen recognition. It is a scavenger receptor, which means it can bind and internalize a wide range of ligands, including oxidized low-density lipoprotein (oxLDL), long-chain fatty acids, and apoptotic cells. CD36 is expressed in a variety of tissues, including platelets, monocytes, macrophages, adipocytes, skeletal muscle, heart muscle, and endothelial cells.

CD36 is part of the class B scavenger receptor family and plays a key role in cellular lipid uptake, particularly the transport of long-chain fatty acids into cells, where they are utilized for energy production or stored as triglycerides. Additionally, CD36 has significant roles in the innate immune system, acting as a pattern recognition receptor (PRR) for various ligands, including microbial components and oxidized lipoproteins, contributing to the body's defense against infections and in the pathogenesis of chronic inflammatory conditions, such as atherosclerosis.

CD36 has been extensively studied due to its implication in metabolic disorders like obesity, insulin resistance, and type 2 diabetes, as well as its involvement in the development of cardiovascular diseases. Understanding the molecular structure and function of CD36 is essential for developing therapeutic strategies to target its role in disease.

Protein Structure

The CD36 molecule is a transmembrane glycoprotein consisting of 472 amino acids with a molecular weight of approximately 88 kDa. The protein's structure is characterized by:

Extracellular Domain:

• The largest portion of the CD36 molecule is extracellular, comprising around 80% of its total length. This domain is heavily glycosylated, with 10 predicted N-glycosylation sites, which contribute to its stability, proper folding, and ligand-binding ability.
• The extracellular domain has a unique structure featuring two large loops connected by the transmembrane regions. These loops are critical for the interaction with a variety of ligands, such as long-chain fatty acids, oxidized LDL, and phospholipids.
• CD36 contains several ligand-binding sites distributed across its extracellular domain. These sites mediate the binding of diverse ligands, including fatty acids and oxidized lipoproteins, which are essential for its roles in lipid uptake and immune responses.

Transmembrane Domains:

• CD36 has two transmembrane domains, one near the N-terminus and one near the C-terminus, anchoring the protein within the lipid bilayer. These hydrophobic transmembrane regions form stable interactions with the cell membrane and play a crucial role in maintaining the protein's structural integrity.
• The transmembrane regions serve as a bridge between the extracellular domain and the short intracellular tails, facilitating intracellular signaling in response to ligand binding.

Intracellular Domains:

• CD36 has short cytoplasmic tails at both the N-terminus and C-terminus, each comprising around 10 amino acids. Although these regions are relatively short, they contain essential motifs for interacting with intracellular adaptor proteins, which are critical for signal transduction.
• These tails interact with signaling molecules such as Src family kinases, protein kinase C (PKC), and other cytoplasmic proteins that mediate downstream signaling pathways involved in fatty acid uptake, inflammation, and cellular metabolism.

The N-terminal and C-terminal tails of CD36 are phosphorylated in response to various stimuli, which influences its localization and function. The heavily glycosylated extracellular loops provide binding sites for a wide variety of ligands, making CD36 highly versatile in mediating different biological processes.

Classification and Subtypes

CD36 is a member of the Class B scavenger receptor family, which includes other related proteins like SR-BI (scavenger receptor class B type I) and LIMP-II (lysosomal integral membrane protein II). The family is characterized by their ability to bind and internalize a wide variety of ligands, including modified lipoproteins, apoptotic cells, and microbial components.

CD36 itself does not have distinct subtypes but exists as a single isoform that can be post-translationally modified, such as glycosylation and phosphorylation, which may alter its function. Additionally, genetic polymorphisms in the CD36 gene, which is located on chromosome 7q11.2, have been linked to variations in CD36 expression levels and function, influencing susceptibility to metabolic diseases and cardiovascular conditions.

Function and Biological Significance

The biological functions of CD36 are diverse, reflecting its ability to bind various ligands and participate in multiple cellular processes. The major roles of CD36 include:

Lipid Metabolism:

• CD36 is critical for the uptake of long-chain fatty acids into cells, particularly in tissues with high energy demands, such as the heart and skeletal muscle. Once fatty acids bind to CD36, they are transported into the cell for beta-oxidation or storage as triglycerides.
• This function is central to energy metabolism and has important implications in conditions like insulin resistance, obesity, and type 2 diabetes. Dysregulation of CD36-mediated fatty acid uptake can lead to lipid accumulation in tissues, contributing to metabolic dysfunction.

Immune Response and Inflammation:

• CD36 functions as a pattern recognition receptor (PRR) for the innate immune system, binding to oxidized low-density lipoprotein (oxLDL), phosphatidylserine on apoptotic cells, and bacterial lipids. This allows CD36 to mediate the phagocytosis of apoptotic cells and clearance of pathogens, contributing to immune defense.
• In macrophages, CD36 promotes the uptake of oxLDL, leading to the formation of foam cells, which are key contributors to the development of atherosclerotic plaques in blood vessels. Thus, CD36 plays a significant role in the progression of atherosclerosis.
• Additionally, CD36 is involved in mediating inflammatory signaling pathways, particularly through interactions with Toll-like receptors (TLRs), which amplify the inflammatory response to pathogens and damaged cells.

Platelet Adhesion and Thrombosis:

• CD36 is expressed on the surface of platelets and plays a role in platelet activation and thrombus formation. It mediates the interaction of platelets with oxidized lipids and apoptotic cells, contributing to thrombosis and vascular complications in diseases like diabetes and atherosclerosis.

Angiogenesis:

• CD36 also functions as an anti-angiogenic receptor, binding to thrombospondin-1 (TSP-1), which inhibits endothelial cell migration and proliferation, thereby suppressing the formation of new blood vessels. This function is important in regulating angiogenesis during development, wound healing, and tumor growth.

Host Defense Against Infections:

• CD36 plays a role in recognizing microbial components and initiating immune responses to infections, particularly in the context of malarial parasite infection. CD36 facilitates the phagocytosis of infected red blood cells and has been implicated in the immune response to Plasmodium falciparum.

Clinical Issues

Given its involvement in critical biological processes, dysregulation of CD36 has been associated with several clinical conditions:

Metabolic Diseases:

• CD36 deficiency or dysregulation is linked to insulin resistance, type 2 diabetes, and obesity. In these conditions, impaired fatty acid uptake leads to lipotoxicity, which contributes to metabolic disturbances and the development of insulin resistance.
• Polymorphisms in the CD36 gene are associated with altered susceptibility to these metabolic disorders, highlighting the importance of CD36 in regulating lipid metabolism.

Cardiovascular Diseases:

• CD36 plays a central role in the development of atherosclerosis by mediating the uptake of oxLDL by macrophages, leading to foam cell formation and plaque development. CD36 expression on platelets and endothelial cells also contributes to vascular inflammation, thrombosis, and coronary artery disease.
• Targeting CD36 has been explored as a therapeutic strategy to reduce plaque formation and prevent the progression of cardiovascular diseases.

Thrombosis:

• CD36's role in platelet activation and thrombus formation has implications for conditions like venous thromboembolism and arterial thrombosis. CD36-deficient individuals show altered platelet function, which could influence their susceptibility to thrombotic disorders.

Infectious Diseases:

• CD36 deficiency has been associated with susceptibility to severe malaria. CD36 plays a role in the clearance of malaria-infected erythrocytes, and genetic polymorphisms affecting CD36 function may influence the course and severity of malaria infection.

Cancer:

• Due to its anti-angiogenic properties, CD36 has been studied in the context of tumor growth. CD36 expression on endothelial cells suppresses angiogenesis, which may limit the blood supply to tumors and inhibit their growth. However, CD36 has also been implicated in the metastatic potential of cancer cells, particularly in promoting the spread of tumors to distant sites through interactions with fatty acids.

Summary

CD36 is a versatile membrane glycoprotein with critical roles in lipid metabolism, immune function, thrombosis, and angiogenesis. Its ability to bind diverse ligands, such as long-chain fatty acids, oxidized lipoproteins, and apoptotic cells, positions CD36 as a central regulator of cellular homeostasis and immune responses. Dysregulation of CD36 contributes to the pathogenesis of metabolic diseases, cardiovascular disorders, thrombosis, and inflammatory conditions. Ongoing research into the structure-function relationship of CD36 and its role in human disease may provide new avenues for therapeutic interventions, particularly in targeting metabolic and cardiovascular diseases.