TY - JOUR
T1 - The Structural Architecture of an Infectious Mammalian Prion Using Electron Cryomicroscopy
AU - Vazquez-Fernandez, Ester
AU - Vos, Matthijn R.
AU - Afanasyev, Pavel
AU - Cebey, Lino
AU - Sevillano, Alejandro M.
AU - Vidal, Enric
AU - Rosa, Isaac
AU - Renault, Ludovic
AU - Ramos, Adriana
AU - Peters, Peter
AU - Jesus Fernandez, Jose
AU - van Heel, Marin
AU - Young, Howard S.
AU - Requena, Jesus R.
AU - Wille, Holger
PY - 2016/9
Y1 - 2016/9
N2 - 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.
AB - 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.
U2 - 10.1371/journal.ppat.1005835
DO - 10.1371/journal.ppat.1005835
M3 - Article
C2 - 27606840
SN - 1553-7366
VL - 12
JO - PLOS PATHOGENS
JF - PLOS PATHOGENS
IS - 9
M1 - e1005835
ER -