Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 7, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2018731118
Keywords
nicotinic acetylcholine receptor; patch clamping; electrical fingerprinting; evolutionary biochemistry; ancestral reconstruction
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Funding
- Canada Graduate Scholarship from the Canadian Institutes of Health Research (CIHR)
- Natural Sciences and Engineering Research Council (NSERC) of Canada CREATE Scholarship
- NSERC Discovery Grant [RGPIN 2019-06864, RGPIN-2016-04801]
- Canada Research Chairs Grant [950-232154]
- CIHR [377068]
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The study found that a single historical amino acid substitution can influence the assembly of muscle-type acetylcholine receptors, thereby increasing receptor complexity. Through a single amino acid substitution, the research revealed that subunit entrenchment can be driven, providing new insights into the evolution of protein subunit complexity.
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 beta-subunit can not only replace the extant beta-subunit but can also supplant the neighboring delta-subunit. By forward evolving the ancestral beta-subunit with a single amino acid substitution, we restore the requirement for a delta-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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