Beta2-Glycoprotein I Binds Thrombin via Exosite I and Exosite II
Objective. Beta2-glycoprotein I (B2GPI) is a dominant antigenic target in antiphospholipid syndrome (APS). Beta2-glycoprotein I may bind to factor XI and serve a physiologic function as a regulator of factor XI activation by thrombin. We undertook this study to investigate the possible interactions of B2GPI with thrombin in B2GPI-regulated factor XI activation by thrombin and to evaluate the effect of anti-B2GPI antibodies on this system. Methods. The B2GPI interaction with thrombin was investigated in direct and competitive assays using B2GPI domain mutants and thrombin-binding exosite oligonucleotides. Beta2-glycoprotein I inhibition of thrombin-mediated factor XI activation was assessed in the presence of 8 anti-B2GPI monoclonal antibodies (mAb) directed against domain I. Results. Domain V of B2GPI was involved in direct binding to thrombin, and exosite I and exosite II on thrombin took part in this interaction. Anti-B2GPI mAb produced a >70% inhibition of thrombin-mediated factor XI activation in the presence of B2GPI.
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