Research Article: Full atomistic model of prion structure and conversion

Date Published: July 11, 2019

Publisher: Public Library of Science

Author(s): Giovanni Spagnolli, Marta Rigoli, Simone Orioli, Alejandro M. Sevillano, Pietro Faccioli, Holger Wille, Emiliano Biasini, Jesús R. Requena, Surachai Supattapone.


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-β-Sheet (PIRIBS) [2] or β-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 β-solenoid (4RβS) [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 4RβS 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 β-solenoid. Importantly, the 4RβS 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.

Partial Text

Prion diseases are infectious neurodegenerative disorders characterized by an invariably lethal outcome caused by a proteinaceous infectious agent named “prion” [1]. The central event in these pathologies is the conversion of PrPC, a GPI-anchored protein of unknown function, into a misfolded isoform (PrPSc) which accumulates in the central nervous system of affected individuals [6]. While PrPC structure has been widely characterized, and consists of a N-terminal disordered tail and a C-terminal globular domain [7], no high-resolution information is available for PrPSc due to technical challenges posed by its high insolubility and aggregation propensity [8]. In order to fill this gap, different atomistic models based on low-resolution experimental data have been proposed, including a Left-handed-β-Helix (LβH) structure spanning residues 89 to 170 while retaining the two C-terminal α-helices of PrPC [9], and a Parallel In-Register Beta-Sheet (PIRIBS) architecture, characterized by intermolecular stacking of aligned PrP monomers [10]. Recent cryo-EM data obtained using infectious, anchorless PrPSc fibrils [4] provided strong evidence indicating that PrPSc fibrils consist of two independent protofilaments, and of the existence of 2 nm structural units repeating along each protofilament axis, suggestive of a 4-rung β-solenoid (4RβS). This would be fully compatible with the LβH model, and much less so with the PIRIBS model, which posits that PrPSc fibrils are not made up by two protofilaments, but rather, by a single wider filament that features two subdomains or lobes separated by a cleft (Goveman et al., 2014). Moreover, the PIRIBS model fails to accommodate glycosylated residues in PrPSc, which would result in the introduction of excessive steric clashes [11]. It should be pointed out, however, that the low resolution of available experimental data still does not allow to definitively discard any option (a detailed comparison of PIRIBS and solenoid-based models can be found in [12]). Of note, while consistent with the mentioned experimental constraints, the proposed LβH model is incoherent with a recent re-evaluation of previous FTIR data suggesting that PrPSc does not contain α-helices [8].

The elucidation of the structure of PrPSc at atomic resolution has proven to be a phenomenal experimental challenge, mainly due to its high insolubility and aggregation propensity. Previously generated computational models of PrPSc have the virtue of providing a plausible 3D structure, but fail to comprehensively accommodate most recent experimental data [8]. Here, we filled this gap by exploiting the information arising from cryo-EM and X-ray fiber-diffraction studies [4, 5], which clearly defined the general architecture of PrPSc as a 4RβS and refined the structure by including experimental constraints obtained by mass spectrometry. The model we have created allowed us to perform the first reconstruction of how the information encoded into the conformation of a protein could be propagated in a directional fashion, a concept directly underlying the infectious nature of prions.




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