on January 15, 2004
Published online before print January 15, 2004, doi: 10.1161/01.ATV.0000117174.19078.85
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Submitted on July 3, 2003
Accepted on December 1, 2003
Molecular Mechanism for Changes in Proteoglycan Binding on Compositional Changes of the Core and the Surface of Low-Density Lipoprotein-Containing Human Apolipoprotein B100
Christofer Flood ;
From the Wallenberg Laboratory for Cardiovascular Research (C.F., M.G., J.B.), The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden; the Gladstone Institute of Cardiovascular Disease (R.E.P., L.A.), Cardiovascular Research Institute and the Department of Pathology (R.E.P.), University of California, San Francisco; and the Department of Poultry Science (R.L.W.), Texas A&M University, Kleberg Center, College Station, TX.
* To whom correspondence should be addressed. E-mail: Jan.Boren{at}wlab.gu.se.
Objective--The aim of this study was to investigate the molecular mechanism for changes in proteoglycan binding and LDL receptor affinity on two compositional changes in LDL that have been associated with atherosclerosis: cholesterol enrichment of the core and modification by secretory group IIA phospholipase A2 (sPLA2) of the surface.
Methods and Results--Transgenic mice expressing recombinant apolipoprotein (apo) B and sPLA2 were generated. Recombinant LDL were isolated and tested for their proteoglycan and LDL receptor-binding activity. The results show site A (residues 3148 to 3158) in apoB100 becomes functional in sPLA2-modified LDL and that site A acts cooperatively with site B (residues 3359 to 3369), the primary proteoglycan-binding site in native LDL, in the binding of sPLA2-modified LDL to proteoglycans. Our results also show that cholesterol enrichment of LDL is associated with increased affinity for proteoglycans and for the LDL receptor. This mechanism is likely mediated by a conformational change of site B and is independent of site A in apoB100.
Conclusion--Site A in apoB100 becomes functional in sPLA2-modified LDL and acts cooperatively with site B resulting in increased proteoglycan-binding activity. The increased binding for proteoglycans of cholesterol-enriched LDL is solely dependent on site B.
Key words: lipoproteins • apolipoprotein B • proteoglycans • atherosclerosis • transgenic mice • phospholipase A2
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