A chimeric prokaryotic pentameric ligand–gated channel reveals distinct pathways of activation
Abstract
Recent high resolution structures of several pentameric ligand–gated ion channels have provided unprecedented details of their molecular architecture. However, the conformational dynamics and structural rearrangements that underlie gating and allosteric modulation remain poorly understood. We used a combination of electrophysiology, double electron–electron resonance (DEER) spectroscopy, and x-ray crystallography to investigate activation mechanisms in a novel functional chimera with the extracellular domain (ECD) of amine-gated Erwinia chrysanthemi ligand–gated ion channel, which is activated by primary amines, and the transmembrane domain of Gloeobacter violaceus ligand–gated ion channel, which is activated by protons. We found that the chimera was independently gated by primary amines and by protons. The crystal structure of the chimera in its resting state, at pH 7.0 and in the absence of primary amines, revealed a closed-pore conformation and an ECD that is twisted with respect to the transmembrane region. Amine- and pH-induced conformational changes measured by DEER spectroscopy showed that the chimera exhibits a dual mode of gating that preserves the distinct conformational changes of the parent channels. Collectively, our findings shed light on both conserved and divergent features of gating mechanisms in this class of channels, and will facilitate the design of better allosteric modulators.
- Authors:
-
- Case Western Reserve Univ., Cleveland, OH (United States). Dept. of Neuroscience
- Case Western Reserve Univ., Cleveland, OH (United States). Dept. of Physiology and Biophysics
- Vanderbilt Univ., Nashville, TN (United States). Dept. of Molecular Physiology and Biophysics
- Case Western Reserve Univ., Cleveland, OH (United States). Dept. of Biochemistry
- Case Western Reserve Univ., Cleveland, OH (United States). Center for Proteomics and Bioinformatics
- Case Western Reserve Univ., Cleveland, OH (United States). Dept. of Neuroscience. Dept. of Physiology and Biophysics
- Publication Date:
- Research Org.:
- Case Western Reserve Univ., Cleveland, OH (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC); National Inst. of Health (NIH) (United States); American Heart Association (United States)
- Contributing Org.:
- Vanderbilt Univ., Nashville, TN (United States)
- OSTI Identifier:
- 1222834
- Grant/Contract Number:
- AC02-06CH11357; 1R01GM108921; 12SDG12070069; U54-GM087519; S10RR027091; R00EY019718; R01DK81567; P41 GM103403
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of General Physiology
- Additional Journal Information:
- Journal Volume: 146; Journal Issue: 4; Journal ID: ISSN 0022-1295
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; 46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND TECHNOLOGY
Citation Formats
Schmandt, Nicolaus, Velisetty, Phanindra, Chalamalasetti, Sreevatsa V., Stein, Richard A., Bonner, Ross, Talley, Lauren, Parker, Mark D., Mchaourab, Hassane S., Yee, Vivien C., Lodowski, David T., and Chakrapani, Sudha. A chimeric prokaryotic pentameric ligand–gated channel reveals distinct pathways of activation. United States: N. p., 2015.
Web. doi:10.1085/jgp.201511478.
Schmandt, Nicolaus, Velisetty, Phanindra, Chalamalasetti, Sreevatsa V., Stein, Richard A., Bonner, Ross, Talley, Lauren, Parker, Mark D., Mchaourab, Hassane S., Yee, Vivien C., Lodowski, David T., & Chakrapani, Sudha. A chimeric prokaryotic pentameric ligand–gated channel reveals distinct pathways of activation. United States. https://doi.org/10.1085/jgp.201511478
Schmandt, Nicolaus, Velisetty, Phanindra, Chalamalasetti, Sreevatsa V., Stein, Richard A., Bonner, Ross, Talley, Lauren, Parker, Mark D., Mchaourab, Hassane S., Yee, Vivien C., Lodowski, David T., and Chakrapani, Sudha. Mon .
"A chimeric prokaryotic pentameric ligand–gated channel reveals distinct pathways of activation". United States. https://doi.org/10.1085/jgp.201511478. https://www.osti.gov/servlets/purl/1222834.
@article{osti_1222834,
title = {A chimeric prokaryotic pentameric ligand–gated channel reveals distinct pathways of activation},
author = {Schmandt, Nicolaus and Velisetty, Phanindra and Chalamalasetti, Sreevatsa V. and Stein, Richard A. and Bonner, Ross and Talley, Lauren and Parker, Mark D. and Mchaourab, Hassane S. and Yee, Vivien C. and Lodowski, David T. and Chakrapani, Sudha},
abstractNote = {Recent high resolution structures of several pentameric ligand–gated ion channels have provided unprecedented details of their molecular architecture. However, the conformational dynamics and structural rearrangements that underlie gating and allosteric modulation remain poorly understood. We used a combination of electrophysiology, double electron–electron resonance (DEER) spectroscopy, and x-ray crystallography to investigate activation mechanisms in a novel functional chimera with the extracellular domain (ECD) of amine-gated Erwinia chrysanthemi ligand–gated ion channel, which is activated by primary amines, and the transmembrane domain of Gloeobacter violaceus ligand–gated ion channel, which is activated by protons. We found that the chimera was independently gated by primary amines and by protons. The crystal structure of the chimera in its resting state, at pH 7.0 and in the absence of primary amines, revealed a closed-pore conformation and an ECD that is twisted with respect to the transmembrane region. Amine- and pH-induced conformational changes measured by DEER spectroscopy showed that the chimera exhibits a dual mode of gating that preserves the distinct conformational changes of the parent channels. Collectively, our findings shed light on both conserved and divergent features of gating mechanisms in this class of channels, and will facilitate the design of better allosteric modulators.},
doi = {10.1085/jgp.201511478},
journal = {Journal of General Physiology},
number = 4,
volume = 146,
place = {United States},
year = {Mon Sep 28 00:00:00 EDT 2015},
month = {Mon Sep 28 00:00:00 EDT 2015}
}
Web of Science
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Works referencing / citing this record:
Pentameric ligand-gated ion channels exhibit distinct transmembrane domain archetypes for folding/expression and function
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