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Interaction of β 2 ‐glycoprotein I with members of the low density lipoprotein receptor family
Author(s) -
PENNINGS M. T. T.,
VAN LUMMEL M.,
DERKSEN R. H. W. M.,
URBANUS R. T.,
ROMIJN R. A.,
LENTING P. J.,
DE GROOT P. G.
Publication year - 2006
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2006.02036.x
Subject(s) - ldl receptor , low density lipoprotein receptor related protein 8 , receptor , chemistry , lipoprotein , low density lipoprotein , apolipoprotein b , very low density lipoprotein , lipoprotein(a) , binding site , platelet , autoantibody , biochemistry , microbiology and biotechnology , biology , cholesterol , antibody , immunology
Summary. 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 ( β 2 GPI) bound to phospholipids. We have previously demonstrated that dimerization of β 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 β 2 GPI, but not monomeric β 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 β 2 GPI and LDL‐R, apoER2′ and VLDL‐R was best described with a one‐site binding model (half‐maximal binding; ∼20 n m for apoER2′ and VLDL‐R and ∼300 n m for LDL‐R), whereas the interaction between dimeric β 2 GPI and LRP or megalin was best described with a two‐site binding model, representing a high‐ (∼3 n m ) and a low‐affinity site (∼0.2 μ m ). Binding to all receptors tested was unaffected by a tryptophane to serine (W316S) substitution in domain V of β 2 GPI, which is known to disrupt the phospholipid binding site of β 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 β 2 GPI can interact with different LDL‐R family members. This interaction is dependent on a binding site within domain V of β 2 GPI, which does not overlap with the phospholipid‐binding site within domain V.