Correlating structural and energetic changes in glycine receptor activation

Scott, Suzanne, Lynch, Joseph W and Keramidas, Angelo (2015) Correlating structural and energetic changes in glycine receptor activation. Journal of Biological Chemistry, 290 9: 5621-5634. doi:10.1074/jbc.M114.616573

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Author Scott, Suzanne
Lynch, Joseph W
Keramidas, Angelo
Title Correlating structural and energetic changes in glycine receptor activation
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 1083-351X
Publication date 2015-02-27
Sub-type Article (original research)
DOI 10.1074/jbc.M114.616573
Open Access Status File (Publisher version)
Volume 290
Issue 9
Start page 5621
End page 5634
Total pages 14
Place of publication Rockville, United States
Publisher American Society for Biochemistry and Molecular Biology Inc.
Language eng
Formatted abstract
Pentameric ligand-gated ion channels (pLGICs) mediate fast chemoelectrical transduction in the nervous system. The mechanism by which the energy of ligand binding leads to current-conducting receptors is poorly understood and may vary among family members. We addressed these questions by correlating the structural and energetic mechanisms by which a naturally occurring M1 domain mutation (α1Q−26′E) enhances receptor activation in homo- and heteromeric glycine receptors. We systematically altered the charge of spatially clustered residues at positions 19′ and 24′, in the M2 and M2-M3 linker domains, respectively, which are known to be critical to efficient receptor activation, on a background of α1Q−26′E. Changes in the durations of single receptor activations (clusters) and conductance were used to determine interaction coupling energies, which we correlated with conformational displacements as measured in pLGIC crystal structures. Presence of the α1Q−26′E enhanced cluster durations and reduced channel conductance in homo- and heteromeric receptors. Strong coupling between α1−26′ and α119′ across the subunit interface suggests an important role in receptor activation. A lack of coupling between α1−26′ and α124′ implies that 24′ mutations disrupt activation via other interactions. A similar lack of energetic coupling between α1−26′ and reciprocal mutations in the β subunit suggests that this subunit remains relatively static during receptor activation. However, the channel effects of α1Q−26′E on α1β receptors suggests at least one α1-α1 interface per pentamer. The coupling-energy change between α1−26′ and α119′ correlates with a local structural rearrangement essential for pLGIC activation, implying it comprises a key energetic pathway in activating glycine receptors and other pLGICs.
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Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2016 Collection
School of Biomedical Sciences Publications
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Citation counts: TR Web of Science Citation Count  Cited 7 times in Thomson Reuters Web of Science Article | Citations
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