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

• 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.

Nyckelord

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

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)