Evolutionary conservation of the lipopolysaccharide binding site of β²-glycoprotein I

Summary

β²-Glycoprotein I (β²GPI) is a highly abundant plasma protein and the major antigen for autoantibodies in the antiphospholipid syndrome. Recently, we have described a novel function of β²GPI as scavenger of lipopolysaccharide (LPS). With this in mind we investigated the conservation of β²GPI in vertebrates and set out to identify the binding site of LPS within β²GPI. The genome sequences of 42 species were surveyed. Surface plasmon resonance (SPR) was performed with peptides to characterise the binding site of β²GPI for LPS. β²GPI could be identified in most tested vertebrates with a high overall amino acid homology of 80% or more in mammals. SPR revealed that a synthesised peptide (LAFWKTDA) from domain V of β²GPI was able to compete for binding of β²GPI to LPS. The AFWKTDA sequence was completely conserved in all mammals. The peptide containing the LPS binding site attenuated the inhibition by β²GPI in a cellular model of LPS-induced tissue factor expression. Other important sites, such as the binding site for anionic phospholipids and the antiphospholipid antibody binding epitope, were also preserved. β²GPI is highly conserved across the animal kingdom, which suggests that the function of β²GPI may be more important than anticipated.

Keywords

Antiphospholipid syndrome - inflammation - protein structure / folding - protein function / activity

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