Conformational dynamics and role of the acidic pocket in ASIC pH-dependent gating.

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Serval ID
serval:BIB_39E189CDEDD9
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Conformational dynamics and role of the acidic pocket in ASIC pH-dependent gating.
Journal
Proceedings of the National Academy of Sciences of the United States of America
Author(s)
Vullo S., Bonifacio G., Roy S., Johner N., Bernèche S., Kellenberger S.
ISSN
1091-6490 (Electronic)
ISSN-L
0027-8424
Publication state
Published
Issued date
04/04/2017
Peer-reviewed
Oui
Volume
114
Number
14
Pages
3768-3773
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Acid-sensing ion channels (ASICs) are proton-activated Na <sup>+</sup> channels expressed in the nervous system, where they are involved in learning, fear behaviors, neurodegeneration, and pain sensation. In this work, we study the role in pH sensing of two regions of the ectodomain enriched in acidic residues: the acidic pocket, which faces the outside of the protein and is the binding site of several animal toxins, and the palm, a central channel domain. Using voltage clamp fluorometry, we find that the acidic pocket undergoes conformational changes during both activation and desensitization. Concurrently, we find that, although proton sensing in the acidic pocket is not required for channel function, it does contribute to both activation and desensitization. Furthermore, protonation-mimicking mutations of acidic residues in the palm induce a dramatic acceleration of desensitization followed by the appearance of a sustained current. In summary, this work describes the roles of potential pH sensors in two extracellular domains, and it proposes a model of acidification-induced conformational changes occurring in the acidic pocket of ASIC1a.
Keywords
Acid Sensing Ion Channels/chemistry, Acid Sensing Ion Channels/genetics, Acid Sensing Ion Channels/metabolism, Binding Sites, Humans, Hydrogen-Ion Concentration, Models, Molecular, Mutation, Protein Structure, Tertiary, Sodium/metabolism, Toxins, Biological/metabolism, acid-sensing ion channel, conformational changes, kinetic model, pH sensing, voltage clamp fluorometry
Pubmed
Web of science
Open Access
Yes
Create date
28/03/2017 17:01
Last modification date
03/10/2020 5:21
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