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From: TSS ()
Subject: Probing prions
Date: June 9, 2005 at 8:48 am PST

Editor's Summary
9 June 2005

Probing prions

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Alzheimer's, prion diseases and other neurodegenerative disorders are associated with insoluble protein fibres called amyloid fibrils. Gathering structural information about these has proved difficult, but three groups now report success with contrasting approaches to the problem. The cover shows the atomic structure of the 'spine' of an amyloid-like fibril formed by the yeast prion protein Sup35. To obtain this structure, Nelson et al. performed X-ray crystallography on amyloid microcrystals. Krishnan and Lindquist used a raft of techniques to study folding of the amyloid core. And Ritter et al. determined the infectious conformation of HET-s prion of a filamentous fungus. Christopher Dobson ponders on what this flood of structural data says about prion and amyloid formation in sickness and in health.

News and Views: Structural biology: Prying into prions
Various aberrant protein forms are the subject of intense research. It is not easy to probe their structures, but studies that have done so provide telling information about their biological properties.

Christopher M. Dobson

doi: 10.1038/435747a

Full Text | PDF (264K)

Nature 435, 765-772 (9 June 2005) | doi: 10.1038/nature03679
Structural insights into a yeast prion illuminate nucleation and strain diversity
Rajaraman Krishnan1 and Susan L. Lindquist1

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Abstract
Self-perpetuating changes in the conformations of amyloidogenic proteins play vital roles in normal biology and disease. Despite intense research, the architecture and conformational conversion of amyloids remain poorly understood. Amyloid conformers of Sup35 are the molecular embodiment of the yeast prion known as [PSI], which produces heritable changes in phenotype through self-perpetuating changes in protein folding. Here we determine the nature of Sup35's cooperatively folded amyloid core, and use this information to investigate central questions in prion biology. Specific segments of the amyloid core form intermolecular contacts in a 'Head-to-Head', 'Tail-to-Tail' fashion, but the 'Central Core' is sequestered through intramolecular contacts. The Head acquires productive interactions first, and these nucleate assembly. Variations in the length of the amyloid core and the nature of intermolecular interfaces form the structural basis of distinct prion 'strains', which produce variant phenotypes in vivo. These findings resolve several problems in yeast prion biology and have broad implications for other amyloids.

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Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA
Correspondence to: Susan L. Lindquist1 Correspondence and requests for materials should be addressed to S.L.L ( Email: Lindquist_admin@wi.mit.edu).

Received 30 December 2004; Accepted 26 April 2005

Abstract | Full Text | PDF (466K) | Supplementary information

Article: Structure of the cross- spine of amyloid-like fibrils
Rebecca Nelson, Michael R. Sawaya, Melinda Balbirnie, Anders Ø. Madsen, Christian Riekel, Robert Grothe and David Eisenberg

doi: 10.1038/nature03680

Abstract

Numerous soluble proteins convert to insoluble amyloid-like fibrils that have common properties. Amyloid fibrils are associated with fatal diseases such as Alzheimer's, and amyloid-like fibrils can be formed in vitro. For the yeast protein Sup35, conversion to amyloid-like fibrils is associated with a transmissible infection akin to that caused by mammalian prions. A seven-residue peptide segment from Sup35 forms amyloid-like fibrils and closely related microcrystals, from which we have determined the atomic structure of the cross- spine. It is a double -sheet, with each sheet formed from parallel segments stacked in register. Side chains protruding from the two sheets form a dry, tightly self-complementing steric zipper, bonding the sheets. Within each sheet, every segment is bound to its two neighbouring segments through stacks of both backbone and side-chain hydrogen bonds. The structure illuminates the stability of amyloid fibrils, their self-seeding characteristic and their tendency to form polymorphic structures.

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Howard Hughes Medical Institute, UCLA-DOE Institute for Genomics and Proteomics, Box 951570, UCLA, Los Angeles, California 90095-1570, USA
Centre for Crystallographic Studies, Department of Chemistry, University of Copenhagen, Universitetsparken 5, DK-2100 KBH, Denmark
European Synchrotron Radiation Facility, B.P. 220, F-38043 Grenoble Cedex, France
Correspondence to: David Eisenberg1 Correspondence and requests for materials should be addressed to D.E. ( Email: david@mbi.ucla.edu).
The structures of GNNQQNY and NNQQNY have been deposited in the Protein Data Bank with accession codes 1yjp and 1yjo, respectively.

Received 18 January 2005; Accepted 25 April 2005

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Abstract | Full Text | PDF (310K) | Supplementary information

Nature 435, 844-848 (9 June 2005) | doi: 10.1038/nature03793

Correlation of structural elements and infectivity of the HET-s prion
Christiane Ritter1,4, Marie-Lise Maddelein2,4, Ansgar B. Siemer3,4, Thorsten Lührs1, Matthias Ernst3, Beat H. Meier3, Sven J. Saupe2 and Roland Riek1

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Prions are believed to be infectious, self-propagating polymers of otherwise soluble, host-encoded proteins1, 2. This concept is now strongly supported by the recent findings that amyloid fibrils of recombinant prion proteins from yeast3, 4, 5, Podospora anserina6 and mammals7 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 infectivity6. 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 -strands constituted by two pseudo-repeat sequences, each forming a -strand-turn--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.

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The Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037, USA
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
ETH Zurich, Physical Chemistry, ETH Honggerberg, 8093 Zurich, Switzerland
*These authors contributed equally to this work
Correspondence to: Roland Riek1 Correspondence and requests for materials should be addressed to R.R. ( Email: riek@salk.edu).

Received 4 March 2005; Accepted 12 May 2005

First paragraph | Full Text | PDF (936K) | Supplementary information

http://www.nature.com/nature/journal/v435/n7043/edsumm/e050609-01.html

TSS




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