Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 289, Issue 5, Pages 3013-3025Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.523050
Keywords
Cys-loop Receptors; Gating; Ion Channels; Membrane Reconstitution; Spectroscopy
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Funding
- American Heart Association Scientist Development Grant [12SDG12070069]
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Background: Allosteric mechanisms in ligand-gated ion-channels (pLGIC) that couple neurotransmitter binding to channel opening are poorly understood. GLIC is an important prokaryotic surrogate. Results: EPR studies at the junctional interface of GLIC reveal structural changes during desensitization. Conclusion: The closed conformation is characterized by extensive intrasubunit interactions at the junctional interface that weaken during desensitization. Significance: These studies elucidate the role of structural dynamics in pLGIC function. Ligand binding at the extracellular domain of pentameric ligand-gated ion channels initiates a relay of conformational changes that culminates at the gate within the transmembrane domain. The interface between the two domains is a key structural entity that governs gating. Molecular events in signal transduction at the interface are poorly defined because of its intrinsically dynamic nature combined with functional modulation by membrane lipid and water vestibules. Here we used electron paramagnetic resonance spectroscopy to delineate protein motions underlying Gloeobacter violaceus ligand-gated ion channel gating in a membrane environment and report the interface conformation in the closed and the desensitized states. Extensive intrasubunit interactions were observed in the closed state that are weakened upon desensitization and replaced by newer intersubunit contacts. Gating involves major rearrangements of the interfacial loops, accompanied by reorganization of the protein-lipid-water interface. These structural changes may serve as targets for modulation of gating by lipids, alcohols, and amphipathic drug molecules.
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