Beta-2-glycoprotein 1 (Apolipoprotein H) in complex with Phosphatidylserine (PS-β2GPI)

Beta-2-glycoprotein 1 (β2GPI), also known as Apolipoprotein H, is a 50 kDa plasma glycoprotein that serves as a primary autoantigen in Antiphospholipid Syndrome (APS). In its circulating form, β2GPI typically adopts a circular, inactive conformation; however, upon binding to negatively charged phospholipids like phosphatidylserine (PS) on activated cell membranes, it undergoes a dramatic conformational change to an open "J" shape (Source: UniProt P02749, PubMed 21622995). This transition exposes a cryptic epitope in Domain I, which is recognized by high-affinity pathogenic autoantibodies. The formation of the PS-β2GPI-antibody complex on the surface of endothelial cells, platelets, and monocytes triggers intracellular signaling pathways, such as the p38 MAPK and NF-κB pathways, leading to the expression of tissue factor and pro-inflammatory cytokines (Source: PubMed 30361616). This prothrombotic environment results in the clinical hallmarks of APS, including recurrent venous or arterial thrombosis and pregnancy-related morbidities. Current drug development, such as the monoclonal antibody TBT-001, focuses on specifically targeting this complex or the exposed Domain I to inhibit autoantibody binding and subsequent cellular activation without the broad immunosuppression or bleeding risks associated with traditional anticoagulants.

Other names

Apolipoprotein HAPOHB2GPIBeta-2-glycoprotein IPS-B2GPI complexPhosphatidylserine-dependent beta-2-glycoprotein I

Therapeutic strategies involve blocking the interaction between pathogenic autoantibodies and the cryptic Domain I epitope of β2GPI that is exposed upon binding to phosphatidylserine (PS), or using antibodies like TBT-001 to neutralize the complex and prevent downstream prothrombotic signaling in endothelial cells and platelets (Source: PubMed 30361616, 21622995).