Journal
STRUCTURE
Volume 25, Issue 8, Pages 1295-+Publisher
CELL PRESS
DOI: 10.1016/j.str.2017.06.005
Keywords
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Funding
- Generalitat de Catalunya
- Erasmus Mundus - Action 2 Program
- Natural Sciences and Engineering Research Council of Canada Discovery Grant [RGPIN-2016-04801]
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Acetylcholine receptors (AChRs) are members of a superfamily of proteins called pentameric ligand-gated ion channels, which are found in almost all forms of life and thus have a rich evolutionary history. Muscle-type AChRs are heteropentameric complexes assembled from four related subunits (alpha, beta, delta, and epsilon). Here we reconstruct the amino acid sequence of a beta subunit ancestor shared by humans and cartilaginous fishes (i.e., Torpedo). Then, by resurrecting this ancestral beta subunit and co-expressing it with human alpha, delta, and epsilon subunits, we show that despite 132 substitutions, the ancestral subunit is capable of forming human/ancestral hybrid AChRs. Whole-cell currents demonstrate that the agonist acetylcholine has reduced potency for hybrid receptors, while single-channel recordings reveal that hybrid receptors display reduced conductance and open probability. Our results outline a promising strategy for studies of AChR evolution aimed at identifying the amino acid origins of AChR structure and function.
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