| First Author | Vázquez-Fernández E | Year | 2016 |
| Journal | PLoS Pathog | Volume | 12 |
| Issue | 9 | Pages | e1005835 |
| PubMed ID | 27606840 | Mgi Jnum | J:257820 |
| Mgi Id | MGI:5914834 | Doi | 10.1371/journal.ppat.1005835 |
| Citation | Vazquez-Fernandez E, et al. (2016) The Structural Architecture of an Infectious Mammalian Prion Using Electron Cryomicroscopy. PLoS Pathog 12(9):e1005835 |
| abstractText | 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 A. 3D reconstructions of these fibrils revealed two distinct protofilaments, and, together with a molecular volume of 18,990 A3, predicted the height of each PrP 27-30 molecule as ~17.7 A. 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. |
