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An A1-A1 mutant with improved binding and inhibition of β2 GPI/antibody complexes in antiphospholipid syndrome.
- Source :
- FEBS Journal; Mar2015, Vol. 282 Issue 5, p864-873, 10p
- Publication Year :
- 2015
-
Abstract
- β2 glycoprotein I (β2 GPI) 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 β2 GPI-binding modules from ApoE receptor 2 (Apo ER2). A1-A1 binds to β2 GPI/antibody complexes, preventing their association with Apo ER2 and anionic phospholipids, and reducing thrombus size in the mouse model of APS. Here, we describe a mutant of A1-A1 (mA1-A1 ND) with improved affinity for β2 GPI. mA1-A1 ND inhibits the binding of β2 GPI to cardiolipin in the presence of anti-β2 GPI 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 β2 GPI/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 β2 GPI. Modeling studies of A1 in a complex with domain V of β2 GPI (β2 GPI- DV) revealed two possible modes of interaction of a ligand-binding module from lipoprotein receptors with β2 GPI- DV. In both orientations, the ligand-binding module interferes with binding of β2 GPI to anionic phospholipids; however, it interacts with two different but overlapping sets of lysine residues in β2 GPI- DV, depending on the orientation. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 1742464X
- Volume :
- 282
- Issue :
- 5
- Database :
- Complementary Index
- Journal :
- FEBS Journal
- Publication Type :
- Academic Journal
- Accession number :
- 101314403
- Full Text :
- https://doi.org/10.1111/febs.13185