Exposure of the APS antigen. The APLA epitope in β₂GPI domain 1, composed at least in part by Arg39-Arg43, may become exposed and recognized by anti-β₂GPI antibodies. Circulating β₂GPI to be largely in a circular conformation (top left), in which this epitope (red dot) is not exposed. Shielding of this epitope may result from interactions between domain 1 (DI) and domain 5 (DV), or possibly by steric effects of carbohydrate residues originating from domains 3 (DIII) and 4 (DIV) (represented by the blue triangle). (A) Depicts “unfolding” of circular β₂GPI to a fishhook-like shape after binding to anionic phospholipid. Binding to this surface is mediated by domain 5 and results in exposure of the domain 1 epitope. Binding of bivalent anti-β₂GPI antibodies to the exposed epitope may then promote functional β₂GPI dimerization. However, to stimulate unactivated cells, this complex would need to dissociate from phospholipid and subsequently bind cellular receptors. (B) Depicts the proposed effect of direct binding of β₂GPI to putative cellular receptors (annexin A2, apoER2, GPIb; green semicircles). Subsequent β₂GPI unfolding and cross-linking by anti-β₂GPI antibodies may activate cells directly through receptor oligomerization. (C) Shows how binding of β₂GPI to cellular receptors may lead to unfolding and subsequent cross-linking by PF4 tetramers depicted in blue. Cross-linking via PF4 might directly activate cells or facilitate the ability of anti-β₂GPI antibodies to cross-link β₂GPI. (D) Shows how partial epitope exposure may be induced by β₂GPI deglycosylation, oxidation, or interactions with proteins and/or proteases derived from infectious agents. Subsequent binding of anti-β₂GPI anti-bodies may then occur coincident with binding of β₂GPI to cellular receptors. Antibody binding may stabilize and promote the unfolded conformation of β₂GPI.