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

Abstract

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 (β2GPI) bound to phospholipids. We have previously demonstrated that dimerization of β2GPI 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 β 2 GPI, but not monomeric β2GPI, 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 β2GPI and LDL-R, apoER2′ and VLDL-R was best described with a one-site binding model (half-maximal binding; ∼20 nm for apoER2′ and VLDL-R and ∼300 nm for LDL-R), whereas the interaction between dimeric β2GPI and LRP or megalin was best described with a two-site binding model, representing a high-(∼3 nm) and a low-affinity site (∼0.2 μm). Binding to all receptors tested was unaffected by a tryptophane to serine (W316S) substitution in domain V of β2GPI, which is known to disrupt the phospholipid binding site of β2GPI. 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 β2 GPI can interact with different LDL-R family members. This interaction is dependent on a binding site within domain V of β2GPI, which does not overlap with the phospholipid- binding site within domain V. © 2006 International Society on Thrombosis and Haemostasis.