Nascent β Structure in the Elongated Hydrophobic Region of a Gerstmann–Sträussler–Scheinker PrP Allele
Bibliographic record
Abstract
Prion diseases are neurodegenerative disorders caused by the misfolding of the cellular prion protein (PrP C ). Gerstmann–Sträussler–Scheinker syndrome is an inherited prion disease with one early-onset allele (HRdup) containing an eight-amino-acid insertion; this LGGLGGYV insert is positioned after valine 129 (human PrP C sequence) in a hydrophobic tract in the natively disordered region. Here we have characterized the structure and explored the molecular motions and dynamics of HRdup PrP and a control allele. High-resolution NMR data suggest that the core of HRdup has a canonical PrP C structure, yet a nascent β-structure is observed in the flexible elongated hydrophobic region of HRdup. In addition, using mouse PrP C sequence, we observed that a methionine/valine polymorphism at codon 128 (equivalent of methionine/valine 129 in human sequence) and oligomerization caused by high protein concentration affects conformational exchange dynamics at residue G130. We hypothesize that with the β-structure at the N-terminus, the hydrophobic region of HRdup can adopt a fully extended configuration and fold back to form an extended β-sheet with the existing β-sheet. We propose that these structures are early chemical events in disease pathogenesis.
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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 | 0.000 |
| 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 | 0.000 | 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".