<p>Conversion of native cellular prion protein (PrP<sup>c</sup>) from an α-helical structure to a toxic and infectious β-sheet structure (PrP<sup>Sc</sup>) is a critical step in the development of prion disease. There are some indications that the formation of PrP<sup>Sc</sup> is preceded by a β-sheet rich PrP (PrP<sup>β</sup>) form which is non-infectious, but is an intermediate in the formation of infectious PrP<sup>Sc</sup>. Furthermore the presence of lipid cofactors is thought to be critical in the formation of both intermediate-PrP<sup>β</sup> and lethal, infectious PrP<sup>Sc</sup>. We previously discovered that the endotoxin, lipopolysaccharide (LPS), interacts with recombinant PrP<sup>c</sup> and induces rapid conformational change to a β-sheet rich structure. This LPS induced PrP<sup>β</sup> structure exhibits PrP<sup>Sc</sup>-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<sup>c</sup> and inducing β-sheet conversion we systematically investigated which chemical components of LPS either bind or induce PrP conversion to PrP<sup>β</sup>. 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.</p
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