title: Correlation of structural elements and infectivity of the HET-s prion.
abstract: Prions are believed to be infectious, self-propagating polymers of otherwise soluble, host-encoded proteins. This concept is now strongly supported by the recent findings that amyloid fibrils of recombinant prion proteins from yeast, Podospora anserina and mammals can induce prion phenotypes in the corresponding hosts. However, the structural basis of prion infectivity remains largely elusive because acquisition of atomic resolution structural properties of amyloid fibrils represents a largely unsolved technical challenge. HET-s, the prion protein of P. anserina, contains a carboxy-terminal prion domain comprising residues 218-289. Amyloid fibrils of HET-s(218-289) are necessary and sufficient for the induction and propagation of prion infectivity. Here, we have used fluorescence studies, quenched hydrogen exchange NMR and solid-state NMR to determine the sequence-specific positions of amyloid fibril secondary structure elements of HET-s(218-289). This approach revealed four beta-strands constituted by two pseudo-repeat sequences, each forming a beta-strand-turn-beta-strand motif. By using a structure-based mutagenesis approach, we show that this conformation is the functional and infectious entity of the HET-s prion. These results correlate distinct structural elements with prion infectivity.
authors.affiliation: The Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Christiane
authors.initials: C
authors.lastname: Ritter
authors.forename: Marie-Lise
authors.initials: ML
authors.lastname: Maddelein
authors.forename: Ansgar B
authors.initials: AB
authors.lastname: Siemer
authors.forename: Thorsten
authors.initials: T
authors.lastname: Lührs
authors.forename: Matthias
authors.initials: M
authors.lastname: Ernst
authors.forename: Beat H
authors.initials: BH
authors.lastname: Meier
authors.forename: Sven J
authors.initials: SJ
authors.lastname: Saupe
authors.forename: Roland
authors.initials: R
authors.lastname: Riek
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D041961:Deuterium Exchange Measurement; D005453:Fluorescence; D005656:Fungal Proteins; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D048468:Podospora / Q000737:chemistry* / Q000235:genetics; D011328:Prions / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011392:Proline / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D000682:Amyloid; D005656:Fungal Proteins; C083891:HET-S protein, Podospora anserina; D011328:Prions; D011392:Proline