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)-glycoprotein I (beta(2)GPI) in autoimmune diseases, thrombosis, atherosclerosis, and inflammatory processes, substantial interest is focused on the interaction of beta(2)GPI with negatively charged ligands, in particular, with acidic phospholipids. In this study, unilamellar vesicles composed of cardiolipin 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 data suggest that beta(2)GPI anchors to the membrane surface with its hydrophobic loop adjacent to the positively charged lysine rich region in domain V. Subsequently, beta(2)GPI penetrates the membrane interfacial headgroup region as indicated by a restriction of the lipid side chain mobility, but without formation of a nonbilayer lipid phase. A structural rearrangement of beta(2)GPI upon lipid binding was detected by microcalorimetry and may result in the exposure of cryptic epitopes located in the complement control protein domains. This lipid-dependent conformational change may induce oligomerization of beta(2)GPI and promote intermolecular associations. Thus, the aggregation tendency of beta(2)GPI may serve as the basis for the formation of a molecular link between cells but may also be an essential feature for binding of autoantibodies and hence determine the role of beta(2)GPI in autoimmune diseases.
Hammel
M
M
Institute of Biophysics and X-ray Structure Research of the Austrian Academy of Sciences, Schmiedlstrasse 6, A-8042 Graz, Austria.
Schwarzenbacher
R
R
Gries
A
A
Kostner
G M
GM
Laggner
P
P
Prassl
R
R
D001053:Apolipoproteins / Q000378:metabolism*; D004134:Dimyristoylphosphatidylcholine; D005454:Fluorescence Polarization; D006023:Glycoproteins / Q000378:metabolism*; D006358:Hot Temperature; D006801:Humans; D008081:Liposomes / Q000378:metabolism*; D008962:Models, Theoretical; D010743:Phospholipids / Q000378:metabolism*; D011489:Protein Denaturation; D012542:Scattering, Radiation; D013050:Spectrometry, Fluorescence; D014965:X-Rays; D053482:beta 2-Glycoprotein I
D001053:Apolipoproteins; D006023:Glycoproteins; D008081:Liposomes; D010743:Phospholipids; D053482:beta 2-Glycoprotein I; D004134:Dimyristoylphosphatidylcholine