The Structural Architecture of an Infectious Mammalian Prion Using Electron Cryomicroscopy
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|Title:||The Structural Architecture of an Infectious Mammalian Prion Using Electron Cryomicroscopy
|Author:||Vázquez Fernández, Ester
Vos, Matthijn R.
Sevillano Mantas, Alejandro Manuel
Peters, Peter J.
Fernández, José Jesús
Van Heel, Marin
Young, Howard S.
Requena, Jesús R.
|Affiliation:||Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas
|Subject:||Electron cryo-microscopy | Prion disease | Amyloid proteins | Animal prion diseases | Crystal structure | Immunohistochemistry | Molecular structure | Protein structure ||
|Date of Issue:||2016-09-08
|Citation:||Vázquez-Fernández E, Vos MR, Afanasyev P, Cebey L, Sevillano AM, Vidal E, et al. (2016) The Structural Architecture of an Infectious Mammalian Prion Using Electron Cryomicroscopy. PLoS Pathog 12(9): e1005835. https://doi.org/10.1371/journal.ppat.1005835
|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|
|Rights:||© 2016 Vázquez-Fernández et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
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Except where otherwise noted, this item's license is described as © 2016 Vázquez-Fernández et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited