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Full atomistic model of prion structure and conversion

Author:
Spagnolli, Giovanni  Rigoli, Marta  Orioli, Simone  Sevillano, Alejandro M.  Faccioli, Pietro  Wille, Holger  Biasini, Emiliano  Requena, Jesus R.  


Journal:
PLOS PATHOGENS


Issue Date:
2019


Abstract(summary):

Prions are unusual protein assemblies that propagate their conformationally-encoded information in absence of nucleic acids. The first prion identified, the scrapie isoform (PrPSc) of the cellular prion protein (PrPC), caused epidemic and epizootic episodes [1]. Most aggregates of other misfolding-prone proteins are amyloids, often arranged in a Parallel-In-Register-beta-Sheet (PIRIBS) [2] or beta-solenoid conformations [3]. Similar folding models have also been proposed for PrPSc, although none of these have been confirmed experimentally. Recent cryo-electron microscopy (cryo-EM) and X-ray fiber-diffraction studies provided evidence that PrPSc is structured as a 4-rung beta-solenoid (4R beta S) [4, 5]. Here, we combined different experimental data and computational techniques to build the first physically-plausible, atomic resolution model of mouse PrPSc, based on the 4R beta S architecture. The stability of this new PrPSc model, as assessed by Molecular Dynamics (MD) simulations, was found to be comparable to that of the prion forming domain of Het-s, a naturally-occurring beta-solenoid. Importantly, the 4R beta S arrangement allowed the first simulation of the sequence of events underlying PrPC conversion into PrPSc. This study provides the most updated, experimentally-driven and physically-coherent model of PrPSc, together with an unprecedented reconstruction of the mechanism underlying the self-catalytic propagation of prions.


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