Role of polysaccharide and lipid in lipopolysaccharide induced prion protein conversion. Issue 6 (1st November 2016)

• Record Type: Journal Article
• Authors: Ladner-Keay, Carol L.; LeVatte, Marcia; Wishart, David S.
• Is Part Of: Prion. Volume 10:Issue 6(2016)
• Page Start: 466
• Page End: 483
• Publication Date: 2016-11-01
• Subjects: β oligomer -- cofactor -- conversion -- fibril -- lipid -- lipid A -- lipopolysaccharide -- prion protein -- protein misfolding; Protein folding -- Periodicals; Prions -- Periodicals; Proteins -- Biotechnology -- Periodicals; 572.633
• DOI: 10.1080/19336896.2016.1254857
• Languages: English
• ISSNs: 1933-6896

Abstract

ABSTRACT: Conversion of native cellular prion protein (PrP c ) from an α-helical structure to a toxic and infectious β-sheet structure (PrP Sc ) is a critical step in the development of prion disease. There are some indications that the formation of PrP Sc is preceded by a β-sheet rich PrP (PrP β ) form which is non-infectious, but is an intermediate in the formation of infectious PrP Sc . Furthermore the presence of lipid cofactors is thought to be critical in the formation of both intermediate-PrP β and lethal, infectious PrP Sc . We previously discovered that the endotoxin, lipopolysaccharide (LPS), interacts with recombinant PrP c and induces rapid conformational change to a β-sheet rich structure. This LPS induced PrP β structure exhibits PrP Sc -like features including proteinase K (PK) resistance and the capacity to form large oligomers and rod-like fibrils. LPS is a large, complex molecule with lipid, polysaccharide, 2-keto-3-deoxyoctonate (Kdo) and glucosamine components. To learn more about which LPS chemical constituents are critical for binding PrP c and inducing β-sheet conversion we systematically investigated which chemical components of LPS either bind or induce PrP conversion to PrP β . We analyzed this PrP conversion using resolution enhanced native acidic gel electrophoresis (RENAGE), tryptophan fluorescence, circular dichroism, electron microscopy and PK resistance. Our results indicate that a minimal version of LPS (called detoxified and partially de-acylated LPS or dLPS) containing a portion of the polysaccharide and a portion of the lipid component is sufficient for PrP conversion. Lipid components, alone, and saccharide components, alone, are insufficient for conversion.