Interaction of β2-glycoprotein I with members of the low density lipoprotein receptor family

The antiphospholipid syndrome (APS) is a non-inflammatory autoimmune disease characterized by arterial and/or venous thrombosis and/or pregnancy morbidity in the presence of autoantibodies that recognize beta2-glycoprotein I (beta(2)GPI) bound to phospholipids. We have previously demonstrated that dimerization of beta(2)GPI by autoantibodies induces platelet activation, involving the platelet receptor apolipoprotein E receptor 2' (apoER2') a receptor belonging to the low-density lipoprotein receptor (LDL-R) family. Here, we show that dimeric beta(2)GPI, but not monomeric beta(2)GPI, interacts with four other LDL-R family members: the LDL-R related protein (LRP), megalin, the LDL-R and the very-low density lipoprotein receptor (VLDL-R). Interaction between dimeric beta(2)GPI and LDL-R, apoER2' and VLDL-R was best described with a one-site binding model (half-maximal binding; similar to 20 nm for apoER2' and VLDL-R and similar to 300 nm for LDL-R), whereas the interaction between dimeric beta(2)GPI and LRP or megalin was best described with a two-site binding model, representing a high- (similar to 3 nm) and a low-affinity site (similar to 0.2 mu m). Binding to all receptors tested was unaffected by a tryptophane to serine (W316S) substitution in domain V of beta(2)GPI, which is known to disrupt the phospholipid binding site of beta(2)GPI. Also deletion of domain I or II left the interaction with the receptors unaffected. Deletion of domain V, however, significantly decreased the affinity for the receptors. In conclusion, our data show that dimeric beta(2)GPI can interact with different LDL-R family members. This interaction is dependent on a binding site within domain V of beta(2)GPI, which does not overlap with the phospholipid-binding site within domain V.