title: The glycosylation-dependent interaction of perlecan core protein with LDL: implications for atherosclerosis.
abstract: Perlecan is a major heparan sulfate (HS) proteoglycan in the arterial wall. Previous studies have linked it to atherosclerosis. Perlecan contains a core protein and three HS side chains. Its core protein has five domains (DI-DV) with disparate structures and DII is highly homologous to the ligand-binding portion of LDL receptor (LDLR). The functional significance of this domain has been unknown. Here, we show that perlecan DII interacts with LDL. Importantly, the interaction largely relies on O-linked glycans that are only present in the secreted DII. Among the five repeat units of DII, most of the glycosylation sites are from the second unit, which is highly divergent and rich in serine and threonine, but has 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 DII on LDL binding. Unlike LDLR, which directs LDL uptake through endocytosis, this study uncovers a novel feature of the perlecan LDLR-like DII in receptor-mediated lipoprotein retention, which depends on its glycosylation. Thus, perlecan glycosylation may play a role in the early LDL retention during the development of atherosclerosis.
authors.affiliation: Center for Human Genetic Research and Cardiovascular Research CenterMassachusetts General Hospital, Boston, MA 02114.
authors.forename: Yu-Xin
authors.initials: YX
authors.lastname: Xu
authors.affiliation: The Glycomics Center, University of New Hampshire, Durham, NH 03824.
authors.forename: David
authors.initials: D
authors.lastname: Ashline
authors.affiliation: Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA 02118.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114.
authors.forename: Carlos
authors.initials: C
authors.lastname: Tassa
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114.
authors.forename: Stanley Y
authors.initials: SY
authors.lastname: Shaw
authors.affiliation: Departments of Medicine Boston University School of Medicine, Boston, MA 02118 Biochemistry, Boston University School of Medicine, Boston, MA 02118.
authors.forename: Katya
authors.initials: K
authors.lastname: Ravid
authors.affiliation: Biochemistry, Boston University School of Medicine, Boston, MA 02118.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Layne
authors.affiliation: The Glycomics Center, University of New Hampshire, Durham, NH 03824.
authors.forename: Vernon
authors.initials: V
authors.lastname: Reinhold
authors.affiliation: Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA 02118.
authors.forename: Phillips W
authors.initials: PW
authors.lastname: Robbins
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D006031:Glycosylation; D006367:HeLa Cells; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008077:Lipoproteins, LDL / Q000378:metabolism*; D018613:Microscopy, Confocal; D016297:Mutagenesis, Site-Directed; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D051381:Rats; D011973:Receptors, LDL / Q000378:metabolism*
chemical_list: D019812:Heparan Sulfate Proteoglycans; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; C071927:perlecan; D019158:N-Acetylneuraminic Acid
keywords: low density lipoprotein; low density lipoprotein receptor; sialic acid