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

ABSTRACT: ?2 glycoprotein I (?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 ?2GPI-binding modules from ApoE receptor 2 (ApoER2). A1-A1 binds to ?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 ?2GPI. mA1-A1ND inhibits the binding of ?2GPI to cardiolipin in the presence of anti-?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 ?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 ?2GPI. Modeling studies of A1 in a complex with domain V of ?2GPI (?2GPI-DV) revealed two possible modes of interaction of a ligand-binding module from lipoprotein receptors with ?2GPI-DV. In both orientations, the ligand-binding module interferes with binding of ?2GPI to anionic phospholipids; however, it interacts with two different but overlapping sets of lysine residues in ?2GPI-DV, depending on the orientation.

SUBMITTER: Kolyada A 

PROVIDER: S-EPMC4351136 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature