{beta}2-Glycoprotein I can exist in two conformations: implications for our understanding of the antiphospholipid syndrome

The antiphospholipid syndrome is defined by the presence of antiphospholipid antibodies in blood of patients with thrombosis or fetal loss. There is ample evidence that beta(2)-glycoprotein I (beta(2)GPI) is the major antigen for antiphospholipid antibodies. The auto-antibodies recognize beta(2)GPI when bound to anionic surfaces and not in solution. We showed by electron microscopy studies, MALDI-TOF MS, LC/MS-MS that beta(2)GPI can exist in at least two different conformations, a circular plasma conformation and an 'activated' open conformation. We also showed with surface plasmon resonance that the closed, circular conformation is maintained by interaction between the first and fifth domain of beta(2)GPI. By changing pH and salt concentration, we were able to convert the conformation of beta(2)GPI from the closed to the open conformation and back. In the activated open conformation, a cryptic epitope in the first domain becomes exposed that enables patient antibodies to bind and form an antibody-beta(2)GPI complex. We also demonstrate that the open conformation of beta(2)GPI prolonged the aPTT when added to normal plasma, while the aPTT is even further prolonged by addition of anti-beta(2)GPI antibodies. The conformational change of beta(2)GPI and the influence of the auto-antibodies may have important consequences for our understanding of the antiphospholipid syndrome