Structures and allosteric motions of Ryanodine Receptor Domains
Bibliographic record
Abstract
Ryanodine Receptors (RyRs) form large (>;2.2 MDa) ion channels that release Ca2+ from the endoplasmic and sarcoplasmic reticulum. They are thus involved in many calcium‐dependent events, including the contraction of skeletal and cardiac muscle. Mutation in the ryr genes can cause severe skeletal muscle disorders and cardiac arrhythmias. Here we present our recent insights in the structure‐function of these membrane protein giants. We have solved crystal structures of multiple domains in the N‐terminal and central regions and mapped the positions of ~100 disease‐causing mutations. By creating pseudo‐atomic models, we analyzed the motions these domains undergo during opening and closing of the pore region. Channel opening includes major motions in the central rim. Incidentally, this area contains a hot spot for disease mutations (>;80 total). In particular, channel opening disrupts an intersubunit interface that contains the largest cluster of mutations. By solving structures of several mutant forms of the domains, we observe that mutations can alter relative domain orientations. They thus mimic the effect of binding of ligands to the related IP3 receptor. Overall, we present a model whereby the N‐terminal region of the RyR serves as a gating ring that forms a hub for allosteric control.
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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 | 0.001 |
| 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 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".