The role of the low-density lipoprotein receptor family in the pathology of the antiphospholipid syndrome

Abstract

The results in this thesis show that the interaction between ß2GPI and LDL-R family members is based on the recognition of a cationic patch within domain V of ß2GPI by LDL-R homologous. Molecular studies have identified a specific region within domain V of ß2GPI (Lys282, Lys284, Lys286 and Lys287) that is recognized by the human platelet receptor apoER2'. Furthermore, the studies demonstrate that the apoER2' recognition site does not overlap the phospholipid-binding site (the flexible loop located at Ser311-Lys317) within domain V of ß2GPI. These observations may learn us how ß2GPI binds to cellular surfaces containing anionic phospholipids. First, low-affinity binding of ß2GPI to anionic phospholipids via the flexible loop located at Ser311-Lys317 occurs, inducing a conformational change within ß2GPI. These structural changes result in binding of anti-ß2GPI antibodies to an exposed epitope in domain I of ß2GPI followed by protein dimerization. Now, high-affinity binding of dimerized ß2GPI to LDL-R family members takes place, probably via the residue Lys282-Lys287 within domain V of ß2GPI. However, several questions still not to be answered. So far, the studies described in this thesis show the relevance of ß2GPI dimerization in cellular activation in in vitro and in biochemical experiments. Animal models, in which thrombosis can be studies, should be used to investigate the physiological role of ß2GPI dimerization. In addition, future studies must be performed to investigate the role of the LDL-R family in ß2GPI/anti- ß2GPI induced thrombosis. This can be accomplished using LDL-R knockout mice.