Journal
CHEMBIOCHEM
Volume 10, Issue 8, Pages 1385-1391Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.200900092
Keywords
allosterism; backbone esters; ion channels; mutagenesis; receptors
Funding
- NIH [NS 34407, NS 11756]
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Long-range communication is essential for the function of members of the Cys-loop family of neurotransmitter-gated ion channels. The involvement of the peptide backbone in binding-induced conformational changes that lead to channel gating in these membrane proteins is an interesting, but unresolved issue. To probe the role of the peptide backbone, we incorporated a series of alpha-hydroxy acid analogues into the beta-sheet-rich extracellular domain of the muscle subtype of the nicotinic acetylcholine receptor, the prototypical Cys-loop receptor. Specifically, mutations were made in beta strands 7 and 10 of the alpha subunit. A number of single backbone mutations in this region were well tolerated. However, simultaneous introduction of two proximal backbone mutations led to surface-expressed, nonfunctional receptors. Together, these data suggest that while the receptor is remarkably robust in its ability to tolerate single amide-to-ester mutations throughout these beta strands, more substantial perturbations to this region have a profound effect on the protein. These results support a model in which backbone movements in the outer beta sheet are important for receptor function.
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