A combined computational and functional approach identifies new residues involved in pH-dependent gating of ASIC1a.

Details

Ressource 1Download: BIB_D29321C6FC02.P001.pdf (3566.83 [Ko])
State: Public
Version: Final published version
Serval ID
serval:BIB_D29321C6FC02
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
A combined computational and functional approach identifies new residues involved in pH-dependent gating of ASIC1a.
Journal
Journal of Biological Chemistry
Author(s)
Liechti L.A., Bernèche S., Bargeton B., Iwaszkiewicz J., Roy S., Michielin O., Kellenberger S.
ISSN
1083-351X[electronic], 0021-9258[linking]
Publication state
Published
Issued date
2010
Volume
285
Number
21
Pages
16315-16329
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Acid-sensing ion channels (ASICs) are key receptors for extracellular protons. These neuronal nonvoltage-gated Na(+) channels are involved in learning, the expression of fear, neurodegeneration after ischemia, and pain sensation. We have applied a systematic approach to identify potential pH sensors in ASIC1a and to elucidate the mechanisms by which pH variations govern ASIC gating. We first calculated the pK(a) value of all extracellular His, Glu, and Asp residues using a Poisson-Boltzmann continuum approach, based on the ASIC three-dimensional structure, to identify candidate pH-sensing residues. The role of these residues was then assessed by site-directed mutagenesis and chemical modification, combined with functional analysis. The localization of putative pH-sensing residues suggests that pH changes control ASIC gating by protonation/deprotonation of many residues per subunit in different channel domains. Analysis of the function of residues in the palm domain close to the central vertical axis of the channel allowed for prediction of conformational changes of this region during gating. Our study provides a basis for the intrinsic ASIC pH dependence and describes an approach that can also be applied to the investigation of the mechanisms of the pH dependence of other proteins.
Keywords
Amino Acid Substitution, Humans, Hydrogen-Ion Concentration, Ion Channel Gating/physiology, Models, Biological, Models, Molecular, Mutagenesis, Site-Directed, Mutation, Missense, Nerve Tissue Proteins/chemistry, Nerve Tissue Proteins/genetics, Protein Structure, Tertiary, Sodium Channels/chemistry, Sodium Channels/genetics
Pubmed
Web of science
Open Access
Yes
Create date
25/08/2010 13:13
Last modification date
20/10/2020 14:41
Usage data