An A1-A1 mutant with improved binding and inhibition of beta 2GPI/antibody complexes in antiphospholipid syndrome

作者：Kolyada Alexey; Karageorgos Ioannis; Mahlawat Pardeep; Beglova Natalia^*

来源：FEBS Journal, 2015, 282(5): 864-873.

DOI：10.1111/febs.13185

• antiphospholipid syndrome
• ApoER2
• ApoH
• lipoprotein receptor
• beta 2GPI

beta 2 glycoprotein I (beta 2GPI) is the most common antigen for autoimmune antibodies in antiphospholipid syndrome (APS). Thrombosis is a clinical feature of APS. We created a molecule (A1-A1) that consists of two identical beta 2GPI-binding modules from ApoE receptor 2 (ApoER2). A1-A1 binds to beta 2GPI/antibody complexes, preventing their association with ApoER2 and anionic phospholipids, and reducing thrombus size in the mouse model of APS. Here, we describe a mutant of A1-A1 (mA1-A1ND) with improved affinity for beta 2GPI. mA1-A1ND inhibits the binding of beta 2GPI to cardiolipin in the presence of anti-beta 2GPI antibodies, and inhibits the binding to phospholipids in plasma samples of APS patients, affecting the clotting time. Reduction of the clotting time demonstrates the presence of soluble beta 2GPI/antibody complexes in patients' plasma. These complexes either already exist in patients' plasma or form rapidly in the proximity to phospholipids. All members of the low-density lipoprotein receptor family bind beta 2GPI. Modeling studies of A1 in a complex with domain V of beta 2GPI (beta 2GPI-DV) revealed two possible modes of interaction of a ligand-binding module from lipoprotein receptors with beta 2GPI-DV. In both orientations, the ligand-binding module interferes with binding of beta 2GPI to anionic phospholipids; however, it interacts with two different but overlapping sets of lysine residues in beta 2GPI-DV, depending on the orientation.

• 出版日期2015-3