Mechanism of the interaction of beta(2)-glycoprotein I with negatively charged phospholipid membranes

In an attempt to understand the multifunctional involvement of beta (2)-gly coprotein I (beta (2)GPI) in autoimmune diseases, thrombosis, atheroscleros is, and inflammatory processes, substantial interest is focused on the inte raction of beta (2)GPI with negatively charged ligands, in particular, with acidic phospholipids. In this study, unilamellar vesicles composed of card iolipin were used as in vitro membrane system to test and further refine a model of interaction based on the crystal structure of beta (2)GPI. The dat a suggest that beta (2)GPI anchors to the membrane surface with its hydroph obic loop adjacent to the positively charged lysine rich region in domain V . Subsequently, beta 2GPI penetrates the membrane interfacial headgroup reg ion as indicated by a restriction of the lipid side chain mobility, but wit hout formation of a nonbilayer lipid phase. A structural rearrangement of b eta (2)GPI upon lipid binding was detected by microcalorimetry and may resu lt in the exposure of cryptic epitopes located in the complement control pr otein domains. This lipid-dependent conformational change may induce oligom erization of beta (2)GPI and promote intermolecular associations. Thus, the aggregation tendency of beta (2)GPI may serve as the basis for the formati on of a molecular link between cells but may also be an essential feature f or binding of autoantibodies and hence determine the role of beta (2)GPI in autoimmune diseases.