Divalent cation and chloride ion sites of chicken acid sensing ion channel 1a elucidated by x-ray crystallography
- Oregon Health & Science Univ., Portland, OR (United States)
- Indiana Univ. School of Medicine, Indianapolis, IN (United States)
Acid sensing ion channels (ASICs) are proton-gated ion channels that are members of the degenerin/epithelial sodium channel superfamily and are expressed throughout central and peripheral nervous systems. ASICs have been implicated in multiple physiological processes and are subject to numerous forms of endogenous and exogenous regulation that include modulation by Ca2+ and Cl- ions. However, the mapping of ion binding sites as well as a structure-based understanding of the mechanisms underlying ionic modulation of ASICs have remained elusive. Here we present ion binding sites of chicken ASIC1a in resting and desensitized states at high and low pH, respectively, determined by anomalous diffraction x-ray crystallography. The acidic pocket serves as a nexus for divalent cation binding at both low and high pH, while we observe divalent cation binding within the central vestibule on the resting channel at high pH only. Moreover, neutralization of residues positioned to coordinate divalent cations via individual and combined Glu to Gln substitutions reduced, but did not extinguish, modulation of proton-dependent gating by Ca2+. Additionally, we demonstrate that anion binding at the canonical thumb domain site is state-dependent and present a previously undetected anion site at the mouth of the extracellular fenestrations on the resting channel. Our results map anion and cation sites on ASICs across multiple functional states, informing possible mechanisms of modulation and providing a blueprint for the design of therapeutics targeting ASICs.
- Research Organization:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Organization:
- National Inst. of General Medical Sciences; National Inst. of Neurological Disorders and Stroke
- Grant/Contract Number:
- 5T32DK007680; 5F31NS096782; 5R01NS038631
- OSTI ID:
- 1468815
- Journal Information:
- PLoS ONE, Vol. 13, Issue 8; ISSN 1932-6203
- Publisher:
- Public Library of ScienceCopyright Statement
- Country of Publication:
- United States
- Language:
- ENGLISH
Web of Science
Accelerated Current Decay Kinetics of a Rare Human Acid-Sensing ion Channel 1a Variant That Is Used in Many Studies as Wild Type
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journal | May 2019 |
Correction: Divalent cation and chloride ion sites of chicken acid sensing ion channel 1a elucidated by x-ray crystallography
|
journal | December 2018 |
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