Mode of interaction between beta2GPI and lipoprotein receptors suggests mutually exclusive binding of beta2GPI to the receptors and anionic phospholipids.
Lipoprotein receptors of the LDLR family serve as clearance receptors for beta2GPI and as signaling receptors for the beta2GPI/antibody complexes in antiphospholipid syndrome. We compared four ligand-binding LA modules from LDLR and ApoER2 for their ability to bind domain V of beta2GPI (beta2GPI-DV). We found that the LA modules capable of binding beta2GPI-DV interact with the same region on beta2GPI-DV using residues at their calcium-coordination site. The structure of a complex between beta2GPI-DV and LA4 of LDLR, solved by molecular docking guided by NMR-derived restraints and extensively validated, represents the general mode of interaction between beta2GPI and lipoprotein receptors. We have shown that beta2GPI-DV cannot simultaneously bind to lipoprotein receptors and anionic phospholipids, suggesting that the association of beta2GPI/anti-beta2GPI antibody complexes with anionic phospholipids will interfere with lipoprotein receptors' signaling in APS.
Lee
Chang-Jin
CJ
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
De Biasio
Alfredo
A
Beglova
Natalia
N
D001665:Binding Sites; D008024:Ligands; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry*; D010743:Phospholipids / Q000737:chemistry* / Q000378:metabolism; D018110:Receptors, Lipoprotein / Q000737:chemistry* / Q000378:metabolism; D053482:beta 2-Glycoprotein I / Q000737:chemistry* / Q000378:metabolism
D008024:Ligands; D046912:Multiprotein Complexes; D010743:Phospholipids; D018110:Receptors, Lipoprotein; D053482:beta 2-Glycoprotein I