The role of the proteoglycan receptor in lipoprotein binding

Abstract

Heparan sulfate proteoglycan can be adsorbed to a methylated silica surface in a monomolecular layer via its transmembrane hydrophobic protein core domain. Due to electrostatic repulsion, its anionic glycosaminoglycan side chains are stretched out into the blood substitute solution representing one receptor site for specific lipoprotein binding through basic amino acid-rich residues within their apolipoproteins. A second lipoprotein binding site has been localized to four copies of LDL receptor repeats of core domain II. The binding process was studied by ellipsometric techniques showing that HDL has a high binding affinity to the receptor and a protective effect on interfacial heparan sulfate proteoglycan layers with respect to LDL and Ca²⁺ complexation. LDL was found to deposit strongly at the proteoheparan sulfate, particularly in the presence of Ca²⁺, thus creating the complex formation ‘proteoglycan—low density lipoprotein—calcium'. This ternary complex build-up may be interpreted as arteriosclerotic nanoplaque formation on the molecular level responsible for the arteriosclerotic primary lesion. On the other hand, HDL bound to heparan sulfate proteoglycan protected against LDL docking and completely suppressed calcification of the proteoglycan-lipoprotein complex. In addition, HDL was able to both reduce the ternary complex deposition and to disintegrate HS-PG/LDL/Ca²⁺ aggregates. Therefore, HDL attached to its proteoglycan receptor sites is thought to raise a multidomain barrier, selection and control motif for transmembrane and paracellular lipoprotein uptake into the arterial wall. Although much remains unclear regarding the mechanism of lipoprotein depositions at proteoglycan-coated surfaces, it seems clear that the use of such systems offers possibilities for investigating lipoprotein deposition at a ‘nanoscopic' level under close to physiological conditions. In particular, Ca²⁺-promoted LDL deposition and the protective effect of HDL, even at high Ca²⁺ and LDL concentrations, agree well with previous clinical observations regarding risk and beneficial factors for early stages of atherosclerosis.