Interaction of beta2-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 (beta2GPI) bound to phospholipids. We have previously demonstrated that dimerization of beta2GPI 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 beta2GPI, but not monomeric beta2GPI, 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 beta2GPI and LDL-R, apoER2' and VLDL-R was best described with a one-site binding model (half-maximal binding; approximately 20 nm for apoER2' and VLDL-R and approximately 300 nm for LDL-R), whereas the interaction between dimeric beta2GPI and LRP or megalin was best described with a two-site binding model, representing a high- (approximately 3 nm) and a low-affinity site (approximately 0.2 microm). Binding to all receptors tested was unaffected by a tryptophane to serine (W316S) substitution in domain V of beta2GPI, which is known to disrupt the phospholipid binding site of beta2GPI. 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 beta2GPI can interact with different LDL-R family members. This interaction is dependent on a binding site within domain V of beta2GPI, which does not overlap with the phospholipid-binding site within domain V.
Pennings
M T T
MT
Department of Haematology, University Medical Center, Utrecht University, Utrecht, the Netherlands.
van Lummel
M
M
Derksen
R H W M
RH
Urbanus
R T
RT
Romijn
R A
RA
Lenting
P J
PJ
de Groot
P G
PG
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D006224:Cricetinae; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D006493:Heparin / Q000737:chemistry; D006801:Humans; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011973:Receptors, LDL / Q000378:metabolism*; D020349:Surface Plasmon Resonance; D013997:Time Factors; D053482:beta 2-Glycoprotein I / Q000097:blood* / Q000737:chemistry / Q000378:metabolism*
D011973:Receptors, LDL; D053482:beta 2-Glycoprotein I; D006493:Heparin