Abstract
Lipoprotein receptors of the LDLR family serve as clearance receptors for beta 2GPI and as signaling receptors for the beta 2GPI/antibody complexes in anti-phospholipid syndrome. We compared four ligand-binding LA modules from LDLR and ApoER2 for their ability to bind domain V of beta 2GPI (beta 2GPI-DV). We found that the LA modules capable of binding beta 2GPI-DV interact with the same region on beta 2GPI-DV using residues at their calcium-coordination site. The structure of a complex between beta 2GPI-DV and LA4 of LDLR, solved by molecular docking guided by NMR-derived restraints and extensively validated, represents the general mode of interaction between beta 2GPI and lipoprotein receptors. We have shown that beta 2GPI-DV cannot simultaneously bind to lipoprotein receptors and anionic phospholipids, suggesting that the association of beta 2GPI/anti-beta 2GPI antibody complexes with anionic phospholipids will interfere with lipoprotein receptors' signaling in APS.