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Probing the role of backbone hydrogen bonding in a critical β sheet of the extracellular domain of a cys-loop receptor

Gleitsman, Kristin R. and Lester, Henry A. and Dougherty, Dennis A. (2009) Probing the role of backbone hydrogen bonding in a critical β sheet of the extracellular domain of a cys-loop receptor. ChemBioChem, 10 (8). pp. 1385-1391. ISSN 1439-4227. PMCID PMC2789490. doi:10.1002/cbic.200900092.

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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 α-hydroxy acid analogues into the β-sheet-rich extracellular domain of the muscle subtype of the nicotinic acetylcholine receptor, the prototypical Cys-loop receptor. Specifically, mutations were made in β strands 7 and 10 of the α 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 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 sheet are important for receptor function.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2009 John Wiley & Sons. Received: February 20, 2009. Published online on April 29, 2009. We thank Dr. Rigo Pantoja for advice and assistance with TIRF measurements. This work was supported by the NIH (NS 34407; NS 11 756). K.R.G. was partially supported by an NSF Graduate Research Fellowship.
Funding AgencyGrant Number
NIHNS 34407
NIHNS 11756
NSF Graduate Research FellowshipUNSPECIFIED
Subject Keywords:allosterism; backbone esters; ion channels; mutagenesis; receptors
Issue or Number:8
PubMed Central ID:PMC2789490
Record Number:CaltechAUTHORS:20090805-085419387
Persistent URL:
Official Citation:Gleitsman, K. R., Lester, H. A. and Dougherty, D. A. (2009), Probing the Role of Backbone Hydrogen Bonding in a Critical β Sheet of the Extracellular Domain of a Cys-Loop Receptor. ChemBioChem, 10: 1385–1391. doi:10.1002/cbic.200900092
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:14807
Deposited By: Tony Diaz
Deposited On:06 Aug 2009 23:45
Last Modified:08 Nov 2021 23:14

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