Bibliographic record
Abstract
<h3>Abstract</h3> Prions are unusual protein assemblies that propagate their conformationally-encoded information in absence of nucleic acids. The first prion identified, the scrapie isoform (PrP<sup>Sc</sup>) of the cellular prion protein (PrP<sup>C</sup>), is the only one known to cause 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 PrP<sup>Sc</sup>, although none of these have been confirmed experimentally. Recent cryo-electron microscopy (cryo-EM) and X-ray fiber-diffraction studies provided evidence that PrP<sup>Sc</sup> 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 PrP<sup>Sc</sup>, based on the 4RβS architecture. The stability of this new PrP<sup>Sc</sup> 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 PrP<sup>C</sup> conversion into PrP<sup>Sc</sup>. Our results provide the most updated, experimentally-driven and physically-coherent model of PrP<sup>Sc</sup>, together with an unprecedented reconstruction of the mechanism underlying the self-catalytic propagation of prions. <h3>Significance</h3> Since the original hypothesis by Stanley Prusiner, prions have represented enigmatic agents diverging from the classical concept of genetic inheritance. However, the structure of PrP<sup>Sc</sup>, the infectious isoform of the cellular prion protein (PrP<sup>C</sup>), has so far remained elusive, mostly due to technical challenges posed by its aggregation propensity. Here, we present a new high resolution model of PrP<sup>Sc</sup> derived from the integration of a wide array of recent experimental constraints. By coupling the information of such model with a newly developed computational method, we reconstructed for the first time the conformational transition of PrP<sup>C</sup> to PrP<sup>Sc</sup>. This study offers a unique workbench for designing therapeutics against prion diseases, and a physically-plausible mechanism explaining how protein conformation could self-propagate.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".