Glycosylation and development of atherosclerosis

Abstract

P is a major heparan sulfate (HS) proteoglycan in the arterial wall. Previous studies have localized perlecan to atherosclerotic lesions and its expression correlates with lesion progression. The retention of atherogenic lipoproteins in the arterial wall is an early step in the development of atherosclerosis and this retention is presumably mediated by the ionic interaction between the negatively charged HS and the basic amino acids of apolipoprotein B-100. Perlecan contains a core protein and three HS side chains. Its core protein has five domains (I-V) with disparate structures and domain II is highly homologous to the ligand-binding portion of low-density lipoprotein receptor (LDLR). The functional significance of this domain has been unknown. Here, we show that the perlecan domain II interacts with LDL. Importantly, the interaction largely relies on O-linked glycans that are only present in the secreted domain II. Among the five repeat units of domain II, most of the glycosylation sites are from the second unit, which is highly divergent and rich in serine/threonine but no cysteine residues. Interestingly, most of the glycans are capped by the negatively charged sialic acids, which are critical for LDL binding. We further demonstrate an additive effect of HS and domain II on LDL binding. Unlike LDLR, which directs LDL uptake through endocytosis, this study uncovers a novel feature of the perlecan LDLR-like domain II in receptor-mediated lipoprotein retention, which depends on its glycosylation. Thus, the arterial perlecan glycosylation may provide an attractive non-lipid target to decrease the progression of atherosclerosis.