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

Vullo, Sabrina and Bonifacio, Gaetano and Roy, Sophie and Johner, Niklaus and Bernèche, Simon and Kellenberger, Stephan. (2017) Conformational dynamics and role of the acidic pocket in ASIC pH-dependent gating. Proceedings of the National Academy of Sciences of the United States of America, 114 (14). pp. 3768-3773.

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Official URL: http://edoc.unibas.ch/54797/

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Acid-sensing ion channels (ASICs) are proton-activated Na(+) 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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Computational & Systems Biology > Bioinformatics (Schwede)
05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Computational Biophysics (Bernèche)
UniBasel Contributors:Bernèche, Simon and Johner, Niklaus
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:National Academy of Sciences
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:19 Oct 2017 09:47
Deposited On:19 Oct 2017 09:47

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