There are several human serum proteins for which no clear role is yet known. Among these is the abundant serum protein beta2-glycoprotein-I (β2GPI), which is known to bind to negatively charged phospholipids as well as to bacterial lipopolysaccharides (LPS), and was therefore proposed to play a role in the immune response. To understand the details of these interactions, a biophysical analysis of the binding of β2GPI to LPS and phosphatidylserine (PS) was performed. The data indicate only a moderate tendency of the protein (1) to influence the LPS-induced cytokine production in vitro, (2) to react exothermally with LPS in a non-saturable way, and (3) to change its local microenvironment upon LPS association. Additionally, we found that the protein binds more strongly to phosphatidylserine (PS) than to LPS. Furthermore, β2GPI converts the LPS bilayer aggregates into a stronger multilamellar form, and reduces the fluidity of the hydrocarbon moiety of LPS due to a rigidification of the acyl chains. From these data it can be concluded that β2GPI plays a role as an immune-modulating agent, but there is much less evidence for a role in immune defense against bacterial toxins such as LPS.
Keywords: Cytokine production; FRET, fluorescence resonance energy transfer spectroscopy; FTIR, Fourier-transform infrared spectroscopy; HDL, high-density lipoproteins; Human glycoprotein β2GPI; ITC, isothermal titration calorimetry; Immune modulation; LAL test; LAL, Limulus amebocyte lysate; LBP, lipopolysaccharide-binding protein; LDL, low-density lipoproteins; LPS, lipopolysaccharides; Lipopolysaccharide; MNC, mononuclear cells; PC, phosphatidylcholine; PS, phosphatidylserine; SAXS, small-angle X-ray scattering; β2GPI, beta2-glycoprotein-I.