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Molecular mechanism for changes in proteoglycan binding on compositional changes of the core and the surface of low-density lipoprotein-containing human apolipoprotein B100

Journal article
Authors Christofer Flood
Maria Gustafsson
R. E. Pitas
L. Arnaboldi
R. L. Walzem
Jan Borén
Published in Arterioscler Thromb Vasc Biol
Volume 24
Issue 3
Pages 564-70
ISSN 1524-4636 (Electronic)
Publication year 2004
Published at Wallenberg Laboratory
Pages 564-70
Language en
Keywords Amino Acid Substitution, Animals, Apolipoprotein B-100, Apolipoproteins B/*chemistry/genetics/metabolism, Arteriosclerosis/metabolism, Cholesterol, LDL/metabolism, Extracellular Matrix Proteins, Humans, Lions/blood, Lipoproteins, LDL/*metabolism, Mice, Mice, Inbred C57BL, Mice, Transgenic, Phospholipases A/metabolism, Protein Binding, Protein Conformation, Protein Interaction Mapping, Protein Structure, Tertiary, Proteoglycans/*metabolism, Receptors, LDL/metabolism, Recombinant Fusion Proteins/chemistry/metabolism, Recombinant Proteins/metabolism, Sequence Deletion, Species Specificity
Subject categories Medical and Health Sciences


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 3148-3158) in apoB100 becomes functional in sPLA2-modified LDL and that site A acts cooperatively with site B (residues 3359-3369), 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. CONCLUSIONS: 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.

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