NR ASQZ
AU Ritter,C.; Maddelein,M.L.; Siemer,A.B.; Lührs,T.; Ernst,M.; Meier,B.H.; Saupe,S.J.; Riek,R.
TI Correlation of structural elements and infectivity of the HET-s prion
QU Nature 2005 Jun 9; 435(7043): 844-8
KI Nature. 2005 Jun 9;435(7043):747-9. PMID: 15944684
PT journal article
AB 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.
MH Amino Acid Sequence; Amyloid/*chemistry/genetics/metabolism; Deuterium Exchange Measurement; Fluorescence; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Sequence Data; Mutation/genetics; Podospora/*chemistry/genetics; Prions/*chemistry/genetics/*metabolism; Proline/genetics/metabolism; Protein Structure, Secondary; Protein Structure, Tertiary; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.
AD Christiane Ritter, Thorsten Lührs, Roland Riek, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037, USA; Marie-Lise Maddelein, Sven J. Saupe, Laboratoire de Génétique Moléculaire des Champignons, Institut de Biochimie et de Génétique Cellulaires, Unité Mixte de Recherche 5095, Centre national de la Recherche Scientifique Université de Bordeaux 2, 33077 Bordeaux Cedex, France; Ansgar B. Siemer, Matthias Ernst, Beat H. Meier, ETH Zürich, Physical Chemistry, ETH Hönggerberg, 8093 Zürich, Switzerland
SP englisch
PO England