Mode of Interaction between β2GPI and Lipoprotein Receptors Suggests Mutually Exclusive Binding of β2GPI to the Receptors and Anionic Phospholipids

SummaryLipoprotein receptors of the LDLR family serve as clearance receptors for β2GPI and as signaling receptors for the β2GPI/antibody complexes in antiphospholipid syndrome. We compared four ligand-binding LA modules from LDLR and ApoER2 for their ability to bind domain V of β2GPI (β2GPI-DV). We found that the LA modules capable of binding β2GPI-DV interact with the same region on β2GPI-DV using residues at their calcium-coordination site. The structure of a complex between β2GPI-DV and LA4 of LDLR, solved by molecular docking guided by NMR-derived restraints and extensively validated, represents the general mode of interaction between β2GPI and lipoprotein receptors. We have shown that β2GPI-DV cannot simultaneously bind to lipoprotein receptors and anionic phospholipids, suggesting that the association of β2GPI/anti-β2GPI antibody complexes with anionic phospholipids will interfere with lipoprotein receptors' signaling in APS.

► The structure of the β2GPI-DV/LA4 complex represents how β2GPI-DV binds LA modules ► LA modules interact with lysines 308, 317, and 282 of β2GPI-DV using residues at their Ca2+-coordination site ► A pair of LA modules efficiently binds β2GPI-DV dimerized by antibody ► β2GPI-DV cannot simultaneously bind to lipoprotein receptors and anionic phospholipids