The His-Gly motif of acid-sensing ion channels resides in a reentrant 'loop' implicated in gating and ion selectivity
- University of California, San Francisco, United States
- Oregon Health and Science University, United States
Abstract
Acid-sensing ion channels (ASICs) are proton-gated members of the epithelial sodium channel/degenerin (ENaC/DEG) superfamily of ion channels and are expressed throughout the central and peripheral nervous systems. The homotrimeric splice variant ASIC1a has been implicated in nociception, fear memory, mood disorders and ischemia. Here we extract full-length chicken ASIC1 (cASIC1) from cell membranes using styrene maleic acid (SMA) copolymer, elucidating structures of ASIC1 channels in both high pH resting and low pH desensitized conformations by single-particle cryo-electron microscopy (cryo-EM). The structures of resting and desensitized channels reveal a reentrant loop at the amino terminus of ASIC1 that includes the highly conserved 'His-Gly' (HG) motif. The reentrant loop lines the lower ion permeation pathway and buttresses the 'Gly-Ala-Ser' (GAS) constriction, thus providing a structural explanation for the role of the His-Gly dipeptide in the structure and function of ASICs.
Data availability
The coordinates and associated cryo-EM map for the desensitized SMA-cASIC1a channel at pH 7.0 have been deposited in the Protein Data Bank and Electron Microscopy Data Bank under the accession codes 6VTK and EMD-21380, respectively. The coordinates and associated cryo-EM map for the resting SMA-cASIC1a channel at pH 8.0 have been deposited in the Protein Data Bank and Electron Microscopy Data Bank under the accession codes 6VTL and EMD-21381, respectively.
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Structure of an acid-sensing ion channel solubilized by styrene maleic acid and in a desensitized state at low pHElectron Microscopy Data Bank, EMD-21380.
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Structure of an acid-sensing ion channel solubilized by styrene maleic acid and in a resting state at high pHElectron Microscopy Data Bank, EMD-21381.
Article and author information
Author details
Funding
National Institute of Neurological Disorders and Stroke (5F31NS096782)
- Nate Yoder
National Institute of Neurological Disorders and Stroke (5R01NS038631)
- Eric Gouaux
National Institutes of Health (U24GM129539)
- Nate Yoder
National Institutes of Health (U24GM129547)
- Nate Yoder
National Institute of Diabetes and Digestive and Kidney Diseases (5T32DK007680)
- Nate Yoder
Tartar Trust
- Nate Yoder
ARCS Foundation
- Nate Yoder
Howard Hughes Medical Institute
- Eric Gouaux
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2020, Yoder & Gouaux
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The His-Gly motif of acid-sensing ion channels resides in a reentrant 'loop' implicated in gating and ion selectivity
eLife 9:e56527.
https://doi.org/10.7554/eLife.56527
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