CD59 - CD59 molecule |Elisa - Clia - Antibody - Protein

Background

CD59, also known as membrane attack complex inhibitory protein (MAC-IP), is a small glycoprotein widely expressed on the surface of various human cells. It functions as a crucial regulator of the complement system, specifically by inhibiting the formation of the membrane attack complex (MAC), a part of the immune defense mechanism that targets pathogens and damaged cells for lysis. CD59 is a member of the complement regulatory proteins (CRP) family and plays a key role in protecting host cells from damage caused by the complement system. It is a glycosylphosphatidylinositol (GPI)-anchored protein, meaning it is tethered to the cell membrane via a GPI anchor rather than spanning the membrane like other transmembrane proteins.

CD59 is expressed on a wide variety of cells, including leukocytes, endothelial cells, epithelial cells, red blood cells, and neurons. It serves an essential protective role, particularly on cells that are frequently exposed to complement activation, such as erythrocytes, helping to prevent self-attack by the immune system. Beyond its role in complement regulation, CD59 has been implicated in additional cellular functions, including T-cell activation, angiogenesis, and potentially tumor progression.

Protein Structure

CD59 is a single-chain glycoprotein consisting of approximately 77 amino acids, with a molecular weight of 18-25 kDa, depending on the degree of glycosylation. The protein has the following key structural features:

Extracellular Domain:

• CD59 has a highly conserved extracellular domain that contains two disulfide bonds, forming a compact and stable structure necessary for its inhibitory function. This domain is primarily responsible for binding to components of the MAC, such as C8 and C9, and preventing their polymerization, thereby inhibiting the formation of a functional membrane attack complex.
• The N-terminal region of the extracellular domain contains the critical complement-inhibitory region, which interacts with the terminal complement components.

Glycosylation:

• CD59 is a glycosylated protein, with N-linked glycosylation sites that contribute to its stability and function. Glycosylation also helps in protecting CD59 from proteolytic degradation and enhances its ability to bind to complement components. These modifications are crucial for the protein’s activity and cell-surface localization.

GPI Anchor:

• CD59 is anchored to the cell membrane via a glycosylphosphatidylinositol (GPI) anchor, which is added post-translationally to the C-terminus of the protein. The GPI anchor allows CD59 to be anchored into the outer leaflet of the lipid bilayer without spanning the membrane.
• The GPI anchor is important for localizing CD59 to lipid rafts, specialized microdomains of the cell membrane that play critical roles in cell signaling and immune responses. Localization to lipid rafts enhances the efficiency of CD59’s inhibitory function.

Binding Regions:

• The extracellular domain of CD59 contains specific binding sites for C8 and C9, components of the terminal complement complex. By binding to these complement proteins, CD59 effectively inhibits the assembly of the MAC, preventing pore formation and subsequent cell lysis.

Classification and Subtypes

CD59 is classified as a complement regulatory protein (CRP), which is a group of proteins involved in regulating the activity of the complement system to prevent damage to host cells. It is a member of the broader family of GPI-anchored proteins, which are tethered to the cell membrane via a lipid anchor.

CD59 does not have major subtypes but may exist in differently glycosylated forms, which can slightly alter its molecular weight depending on the cell type. These glycosylation variants do not significantly affect its function but may influence its stability and localization on the cell membrane.

Function and Biological Significance

The primary function of CD59 is to inhibit the formation of the membrane attack complex (MAC), which is a critical effector mechanism of the complement system. The MAC forms as a result of complement activation and is responsible for lysing pathogen membranes or compromised host cells. The complement system can be activated via three pathways: classical, lectin, and alternative pathways, all converging at the formation of the MAC. CD59 plays a crucial role in regulating this final step by binding to C8 and C9, components of the terminal complement complex, and preventing their polymerization.

Key roles and functions of CD59 include:

Inhibition of MAC Formation:

• CD59 binds to the C8 and C9 components of the MAC, preventing the final assembly of the complex. This inhibition stops the formation of transmembrane pores in host cells, thus protecting them from complement-mediated lysis. Without CD59, the unregulated formation of MAC can lead to host cell destruction, which would be harmful in tissues constantly exposed to complement activation, such as blood vessels and epithelial surfaces.

Protection of Host Cells:

• CD59 provides critical protection for a variety of host cells, including red blood cells (RBCs), endothelial cells, and neurons, from complement-mediated damage. Its expression on these cells is essential for maintaining tissue integrity, particularly in environments where complement activation is frequent, such as the bloodstream and areas of inflammation.

Role in Immune Modulation:

• Beyond its role in inhibiting the complement system, CD59 has been suggested to modulate immune responses. It may be involved in T-cell activation and signaling pathways that regulate the adaptive immune response. CD59 is found in lipid rafts, which are known to organize signaling molecules during immune cell activation. Its role in T-cell signaling, though not fully elucidated, points to broader implications for immune regulation.

Other Functions:

• CD59 has also been implicated in angiogenesis and tumor growth. In certain cancer types, CD59 is overexpressed, which may help tumor cells evade complement-mediated destruction. This suggests a potential dual role for CD59 in both immune protection and immune evasion, particularly in the context of tumor biology.

Clinical Issues

Dysfunction or abnormal regulation of CD59 can lead to various clinical issues, especially in the context of complement-related diseases. Some notable clinical associations include:

Paroxysmal Nocturnal Hemoglobinuria (PNH):

• PNH is a rare, acquired hemolytic disorder characterized by the destruction of red blood cells (hemolysis). In PNH, mutations in the PIGA gene lead to a deficiency of GPI-anchored proteins, including CD59 and CD55, on the surface of red blood cells. The absence of CD59 leads to uncontrolled MAC formation and complement-mediated lysis of red blood cells, resulting in chronic hemolysis, hemoglobinuria, and a variety of complications, including thrombosis.

Autoimmune Diseases:

• Reduced expression or function of CD59 has been implicated in the pathogenesis of autoimmune diseases, such as multiple sclerosis (MS) and rheumatoid arthritis. In these diseases, the lack of effective complement regulation may contribute to tissue damage through unregulated complement activation.

Cancer:

• In certain cancers, CD59 is overexpressed, which may allow tumor cells to escape immune destruction by inhibiting complement activation. High levels of CD59 have been observed in various tumor types, including breast cancer, colon cancer, and ovarian cancer, and may correlate with poor prognosis due to immune evasion.

Neurological Disorders:

• CD59 is also expressed in the central nervous system (CNS), where it helps protect neurons from complement-mediated damage. Deficiencies in CD59 have been associated with neurodegenerative conditions like Alzheimer’s disease, where complement activation is believed to play a role in neuronal injury.

Summary

CD59 is a critical complement regulatory protein that protects host cells from complement-mediated lysis by inhibiting the formation of the membrane attack complex (MAC). It is a GPI-anchored glycoprotein with a highly conserved extracellular domain responsible for binding to C8 and C9, preventing their polymerization into a functional MAC. CD59 plays a significant role in immune regulation and has been implicated in a variety of conditions, including PNH, autoimmune diseases, cancer, and neurodegenerative disorders. Understanding the structure and function of CD59 provides insights into its essential role in maintaining immune homeostasis and preventing inappropriate immune responses.