The His-Gly motif of acid-sensing ion channels resides in a reentrant 'loop' implicated in gating and ion selectivity

Abstract
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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.

The following data sets were generated

1. Yoder N
2. Gouaux E
(2020) Structure of an acid-sensing ion channel solubilized by styrene maleic acid and in a desensitized state at low pH
Protein Data Bank, 6VTK.

https://www.rcsb.org/structure/6VTK
1. Yoder N
2. Gouaux E
(2020) Structure of an acid-sensing ion channel solubilized by styrene maleic acid and in a desensitized state at low pH
Electron Microscopy Data Bank, EMD-21380.

https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-21380
1. Yoder N
2. Gouaux E
(2020) Structure of an acid-sensing ion channel solubilized by styrene maleic acid and in a resting state at high pH
Protein Data Bank, 6VTL.

https://www.rcsb.org/structure/6VTL
1. Yoder N
2. Gouaux E
(2020) Structure of an acid-sensing ion channel solubilized by styrene maleic acid and in a resting state at high pH
Electron Microscopy Data Bank, EMD-21381.

https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-21381

Article and author information

Author details

Nate Yoder

Department of Physiology, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-9017-0673
Eric Gouaux

Vollum Institute, Oregon Health and Science University, Portland, United States

For correspondence
gouauxe@ohsu.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8549-2360

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

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.