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PLoS Pathog. 2016 Sep 8;12(9):e1005835. doi: 10.1371/journal.ppat.1005835. eCollection 2016 Sep.

The Structural Architecture of an Infectious Mammalian Prion Using Electron Cryomicroscopy.

Author information

1
Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
2
Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada.
3
FEI Company, Nanoport Europe, Eindhoven, The Netherlands.
4
Institute of Biology Leiden, NeCEN, Leiden, The Netherlands.
5
The Maastricht Multimodal Molecular Imaging Institute, Maastricht University, Maastricht, The Netherlands.
6
CIMUS Biomedical Research Institute University of Santiago de Compostela-IDIS, Santiago de Compostela, Spain.
7
IRTA, Centre de Recerca en Sanitat Animal (CReSA, IRTA-UAB), Campus de la Universitat Autònoma de Barcelona, Bellaterra, Catalonia, Spain.
8
Centro Nacional de Biotecnologia - CSIC, Campus Universidad Autónoma, Madrid, Spain.
9
Brazilian Nanotechnology National Laboratory - LNNano, CNPEM, Campinas, São Paulo, Brazil.
10
Faculty of Natural Science, Imperial College London, London, United Kingdom.

Abstract

The structure of the infectious prion protein (PrPSc), which is responsible for Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy, has escaped all attempts at elucidation due to its insolubility and propensity to aggregate. PrPSc replicates by converting the non-infectious, cellular prion protein (PrPC) into the misfolded, infectious conformer through an unknown mechanism. PrPSc and its N-terminally truncated variant, PrP 27-30, aggregate into amorphous aggregates, 2D crystals, and amyloid fibrils. The structure of these infectious conformers is essential to understanding prion replication and the development of structure-based therapeutic interventions. Here we used the repetitive organization inherent to GPI-anchorless PrP 27-30 amyloid fibrils to analyze their structure via electron cryomicroscopy. Fourier-transform analyses of averaged fibril segments indicate a repeating unit of 19.1 Å. 3D reconstructions of these fibrils revealed two distinct protofilaments, and, together with a molecular volume of 18,990 Å3, predicted the height of each PrP 27-30 molecule as ~17.7 Å. Together, the data indicate a four-rung β-solenoid structure as a key feature for the architecture of infectious mammalian prions. Furthermore, they allow to formulate a molecular mechanism for the replication of prions. Knowledge of the prion structure will provide important insights into the self-propagation mechanisms of protein misfolding.

PMID:
27606840
PMCID:
PMC5015997
DOI:
10.1371/journal.ppat.1005835
[Indexed for MEDLINE]
Free PMC Article

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