Heteropentameric architecture predisposes functional inequivalence of acetylcholine receptor agonist sites
Bibliographic record
Abstract
Muscle-type acetylcholine receptors are heteropen-tameric ion channels composed of four different but evolutionarily related subunits. These subunits assemble with a precise stoichiometry and arrangement, such that two distinct agonist-binding sites are formed at interfaces between a principal α-subunit and a complementary δ or ε/γ-subunit. Chemical differences between the two complementary subunits are presumed to confer functional inequivalence to the two agonist sites. This interpretation, however, overlooks the asymmetric architecture of the acetylcholine receptor, which places each subunit, and therefore each agonist site, at unique positions within the heteropentamer. The extent to which functional inequivalence of the agonist sites stems from this structural asymmetry, as opposed to chemical differences, remains unexplored. Here, we reconstruct an ancestral subunit capable of substituting for both complementary subunits, thereby engineering hybrid ancestral/human acetylcholine receptors with chemically identical agonist sites. Despite being chemically identical, these agonist sites remain functionally inequivalent. We show that this functional inequivalence stems from distinct intersubunit interactions dictated by the receptor’s heteropentameric architecture, which also underlie the subunit-dependent effects of a human disease-causing mutation. Thus, structural asymmetry emerges as a fundamental determinant of receptor function, capable of imposing functional inequivalence even in chemically identical sites, with implications for both the evolution of heteromeric protein complexes and the molecular basis of disease.
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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".