Dynamic Equilibria between Monomeric and Oligomeric Misfolded States of the Mammalian Prion Protein Measured by <sup>19</sup> F NMR
Bibliographic record
Abstract
The assembly of misfolded proteins is a critical step in the pathogenesis of amyloid and prion diseases, although the molecular mechanisms underlying this phenomenon are not completely understood. Here, we use (19)F NMR spectroscopy to examine the thermodynamic driving forces surrounding formation of β-sheet-rich oligomers early in the misfolding and aggregation pathway of the mammalian prion protein. We show that initial assembly of a small octameric intermediate is entropically driven, while further assembly to putative prefibrillar aggregates is driven by a favorable change in enthalpy. Kinetic data suggest that formation of the β-octamer represents a rate-limiting step in the assembly of prion aggregates. A disease-related mutation (F198S) known to destabilize the native state of PrP was also found to stabilize the β-octamer, suggesting that it can influence susceptibility to prion disease through two distinct mechanisms. This study provides new insight into the misfolding pathway leading to critical oligomers of the prion protein and suggests a physical basis for increased assembly of the F198S mutant.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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 source (direct Gemma or distilled Codex), 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".