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

Çetin Ağar; Philip G. de Groot; J. Arnoud Marquart; Joost C. M. Meijers

doi:10.1160/TH11-05-0333

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2011; 106(06): 1069-1075
DOI: 10.1160/TH11-05-0333

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

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

Çetin Ağar

¹Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

²Department of Clinical Chemistry and Haematology, University Medical Center, Utrecht, the Netherlands

,

Philip G. de Groot

²Department of Clinical Chemistry and Haematology, University Medical Center, Utrecht, the Netherlands

,

J. Arnoud Marquart

¹Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

,

Joost C. M. Meijers

¹Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

³Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

› Author Affiliations

Abstract

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

Full Text

References

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