Identification of the binding site for fondaparinux on Beta2-glycoprotein I.

ABSTRACT: Antiphospholipid syndrome (APS) is an autoimmune disease with clinical manifestations of thrombosis and pregnancy complications. Beta2-glycoprotein I (?2GPI) is the major antigen for the APS-related antibodies. Heparin, low-molecular weight heparin and the synthetic pentasaccharide fondaparinux are commonly used for prophylaxis and treatment of thrombosis in patients with antiphospholipid syndrome. These antithrombotic drugs bind and activate antithrombin III to inactivate blood clotting proteases. Heparin and heparin derivatives might have a direct beneficial effect in APS via binding to ?2GPI and interfering with prothrombotic properties of ?2GPI/antibody complexes. We compared fondaparinux to heparin regarding its ability to bind ?2GPI and inhibit the binding of ?2GPI/antibody complexes to negatively charged phospholipids and endothelial cells. Although heparin and fondaparinux bind ?2GPI at therapeutically relevant doses, neither fondaparinux nor heparin was efficient in inhibition of the binding of ?2GPI/antibody complexes to negatively charged phospholipids and endothelial cells. Our studies suggest that these drugs do not act on pathological properties of ?2GPI/antibody complexes, emphasizing the need for a new treatment specific for ?2GPI-related thrombosis in APS. We observed that the binding interface of fondaparinux on ?2GPI does not include the lysine residues known to be critical for binding of heparin. The docking model of the ?2GPI complex with fondaparinux is in agreement with multiple experimental observations.

SUBMITTER: Kolyada A 

PROVIDER: S-EPMC3775933 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature