The Structural Architecture of an Infectious Mammalian Prion Using Electron Cryomicroscopy

Ester Vazquez-Fernandez, Matthijn R. Vos, Pavel Afanasyev, Lino Cebey, Alejandro M. Sevillano, Enric Vidal, Isaac Rosa, Ludovic Renault, Adriana Ramos, Peter Peters, Jose Jesus Fernandez, Marin van Heel, Howard S. Young*, Jesus R. Requena*, Holger Wille*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

92 Citations (Web of Science)

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 angstrom. 3D reconstructions of these fibrils revealed two distinct protofilaments, and, together with a molecular volume of 18,990 angstrom(3), predicted the height of each PrP 27-30 molecule as similar to 17.7 angstrom. Together, the data indicate a four-rung beta-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.
Original languageEnglish
Article numbere1005835
JournalPLOS PATHOGENS
Volume12
Issue number9
DOIs
Publication statusPublished - Sep 2016

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