ArticleProceedings of the National Academy of Sciences of the United States of America2021
A single historical substitution drives an increase in acetylcholine receptor complexity.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Evolutionary causes and consequences of gene duplication.Nature reviews. Genetics · 2026Review
- Phenotypic dominance emerges from activity fitness functions and molecular interactions.Genetics · 2026Article
- Symmetry facilitated the evolution of heterospecificity and high-order stoichiometry in vertebrate hemoglobin.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Layered entrenchment maintains essentiality in the evolution of Form I Rubisco complexes.The EMBO journal · 2025Article
- Symmetry facilitated the evolution of heterospecificity and high-order stoichiometry in vertebrate hemoglobin.bioRxiv : the preprint server for biology · 2024Article
- Mutational biases favor complexity increases in protein interaction networks after gene duplication.Molecular systems biology · 2024Article
- Unusual Evolution of Cephalopod Tryptophan Indole-Lyases.Journal of molecular evolution · 2023Article
- A hierarchical assembly pathway directs the unique subunit arrangement of TRiC/CCT.Molecular cell · 2023Article
- Derepression may masquerade as activation in ligand-gated ion channels.Nature communications · 2023Article
- Simple mechanisms for the evolution of protein complexity.Protein science : a publication of the Protein Society · 2022Review
- Ancestral acetylcholine receptor β-subunit forms homopentamers that prime before opening spontaneously.eLife · 2022Article
- Native mass spectrometry analyses of chaperonin complex TRiC/CCT reveal subunit N-terminal processing and re-association patterns.Scientific reports · 2021Article
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8 authors.
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Abstract
Human adult muscle-type acetylcholine receptors are heteropentameric ion channels formed from four different, but evolutionarily related, subunits. These subunits assemble with a precise stoichiometry and arrangement such that two chemically distinct agonist-binding sites are formed between specific subunit pairs. How this subunit complexity evolved and became entrenched is unclear. Here we show that a single historical amino acid substitution is able to constrain the subunit stoichiometry of functional acetylcholine receptors. Using a combination of ancestral sequence reconstruction, single-channel electrophysiology, and concatenated subunits, we reveal that an ancestral β-subunit can not only replace the extant β-subunit but can also supplant the neighboring δ-subunit. By forward evolving the ancestral β-subunit with a single amino acid substitution, we restore the requirement for a δ-subunit for functional channels. These findings reveal that a single historical substitution necessitates an increase in acetylcholine receptor complexity and, more generally, that simple stepwise mutations can drive subunit entrenchment in this model heteromeric protein.
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