Apolipoprotein H

PDB 1g4g EBI

Apolipoprotein H (Apo-H), also known as beta-2-glycoprotein I (β2GPI), is a protein that in humans is encoded by the APOH gene. Apo-H has a crucial role in the blood coagulation system and is associated with the pathogenesis of several autoimmune diseases, including antiphospholipid syndrome (APS). This protein acts as an inhibitor of coagulation by binding to phospholipids on the surface of platelets and cells, which prevents the conversion of prothrombin to thrombin, a key step in the coagulation cascade.

Structure

Apolipoprotein H is a single-chain glycoprotein with a molecular weight of approximately 50 kDa. It is composed of five domains, known as sushi domains or complement control protein (CCP) modules. These domains are involved in binding negatively charged molecules, including phospholipids and heparin. The fifth domain is particularly important for the binding to cardiolipin, a phospholipid that is exposed on the surface of cells undergoing apoptosis, and to the negatively charged phospholipids involved in the coagulation cascade.

Function

The primary function of Apo-H is to regulate the blood coagulation system. It binds to phospholipids on the surface of cells and platelets, inhibiting the formation of the prothrombinase complex and thus the conversion of prothrombin to thrombin. This action helps to prevent excessive clot formation and thrombosis. Additionally, Apo-H has been implicated in the process of clearing apoptotic cells by binding to phospholipids exposed on their surface.

Clinical Significance

Apolipoprotein H has been associated with several autoimmune and clotting disorders. High levels of antibodies against Apo-H, specifically against the domain that binds cardiolin, are found in patients with antiphospholipid syndrome (APS), a disorder characterized by recurrent venous or arterial thrombosis and pregnancy complications. These antibodies, known as antiphospholipid antibodies (aPL), contribute to the hypercoagulable state seen in APS by interfering with the inhibitory function of Apo-H on the coagulation cascade.

In addition to APS, elevated levels of Apo-H antibodies have been observed in other autoimmune diseases, such as systemic lupus erythematosus (SLE) and in individuals with recurrent miscarriages. The presence of these antibodies is used as a diagnostic marker for APS and has implications for the management and treatment of patients with this condition.

Genetics

The APOH gene is located on chromosome 17q24.2 and consists of 8 exons. Variations in this gene have been studied in the context of their association with susceptibility to autoimmune diseases and thrombotic disorders. However, the relationship between genetic variations in APOH and disease risk remains an area of ongoing research.

Conclusion

Apolipoprotein H is a vital component of the blood coagulation system, with significant implications for autoimmune and thrombotic disorders. Its role in inhibiting coagulation and in the clearance of apoptotic cells highlights the complex interplay between the coagulation system and the immune system. Understanding the mechanisms by which Apo-H functions and its involvement in disease pathogenesis may lead to improved diagnostic and therapeutic strategies for conditions such as antiphospholipid syndrome and systemic lupus erythematosus.