B2GPI COMPLEXES

Brookhaven Science Assoc-Brookhaven Lab, Upton NY

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of this study is to establish the structural rationale for the development of effective and safe treatments of beta2-glycoprotein I (b2GPI)-dependent antiphospholipid syndrome (APS). APS is associated with recurrent thrombosis. The pathology of APS is complex but it is clear that autoimmune antiphospholipid antibodies (aPL) directed against proteins that bind anionic phospholipid play an important role in the disease. b2GPI is a major target of aPL. b2GPI acquires pathological properties after dimerization by autoimmune antibodies that increase its local concentration, promoting interactions with other proteins and cell membranes. Blocking interactions of b2GPI with these proteins or cell surface receptors may mitigate the pathological effect of the aPL. To design an inhibitor it is important to know structural details of the binding interface in the complex. There is no structural information available for any b2GPI complexes. X-ray crystallography is used to determine the structures at the binding interfaces of b2GPI complexes with thrombin, plasminogen and ApoER2. Peptide inhibitors of complex formation will be designed and optimized based on structural information about the contact surfaces in the protein complexes. The peptide inhibitors may provide a starting point for development of non-peptide b2GPI antagonists for potential pharmacological applications, and may be used as a research tool in investigation of a physiologic role of b2GPI in hemostasis and its pathologic role in APS.