CD46

CD46, also known as Membrane Cofactor Protein (MCP), is a regulatory protein expressed on the surface of all cells except erythrocytes. It is involved in the protection of host cells from damage by the complement system, a part of the immune system that helps clear pathogens from an organism. CD46 functions by serving as a cofactor for the inactivation of C3b and C4b by serine proteases in the complement system. This inactivation is crucial for preventing the complement system from attacking the body's own cells.

Structure and Function

CD46 is a type I transmembrane protein that belongs to the regulators of complement activation (RCA) family. It consists of four short consensus repeat (SCR) domains, a serine/threonine/proline-rich (STP) region, a transmembrane domain, and a cytoplasmic tail. The SCR domains are responsible for binding to C3b and C4b, thereby inhibiting their activity.

The protein plays a significant role in the protection of cells from complement-mediated lysis. It does this by acting as a cofactor for factor I, which cleaves C3b and C4b, leading to their inactivation and preventing the formation of the C5 convertase, a complex that can initiate cell lysis.

Clinical Significance

Alterations in CD46 expression or function have been associated with several diseases. For example, mutations in the CD46 gene can lead to atypical hemolytic-uremic syndrome (aHUS), a rare disease characterized by hemolytic anemia, acute renal failure, and thrombocytopenia. CD46 also plays a role in the pathogenesis of certain infections; some pathogens, such as the Measles virus, have developed mechanisms to bind CD46 and use it as a means to enter cells.

Furthermore, CD46 is involved in the regulation of the adaptive immune system. It has been shown to provide a costimulatory signal for T cells, influencing their activation and proliferation. This interaction between CD46 and T cells is an area of active research, with implications for autoimmune diseases and vaccine development.

Genetics

The CD46 gene is located on the short arm of chromosome 1 (1q32). It is highly polymorphic, which means there are many different genetic variants of the gene in the human population. These polymorphisms can affect the function of the CD46 protein and have been studied in the context of susceptibility to diseases, including autoimmune disorders and infections.

Therapeutic Applications

Given its role in regulating the complement system and immune responses, CD46 is a target for therapeutic intervention in diseases characterized by excessive complement activation, such as aHUS and age-related macular degeneration (AMD). Therapeutic strategies include the development of drugs that can enhance CD46 function or mimic its activity, thereby providing protection against complement-mediated damage.

Research Directions

Research on CD46 continues to uncover its complex roles in the immune system and its implications for disease. Studies are exploring how CD46 interacts with other components of the immune system, its role in cancer, and how its function can be modulated for therapeutic purposes.