| Title: | Allosteric coupling between transmembrane segment 4 and the selectivity filter of TALK1 potassium channels regulates their gating by extracellular pH |
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| Authors: | ID Tsai, Wen-Hao (Author)
ID Grauffel, Cédric (Author)
ID Huang, Yueh-Ming (Author)
ID Postić, Sandra (Author)
ID Rupnik, Marjan (Author)
ID Lim, Carmay (Author)
ID Yang, Shi-Bing (Author) |
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| Files: |  RAZ_Tsai_Wen-Hao_2022.pdf (2,78 MB)
MD5: 8A747359C9C34EC7B790D5C597BCAEC5
 https://doi.org/10.1016/j.jbc.2022.101998
https://www.jbc.org/article/S0021-9258(22)00438-0/fulltext
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| Language: | English |
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| Work type: | Scientific work |
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| Typology: | 1.01 - Original Scientific Article |
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| Organization: | MF - Faculty of Medicine
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| Abstract: | Opening of two-pore domain K+ channels (K2Ps) is regulated by various external cues, such as pH, membrane tension, or temperature, which allosterically modulate the selectivity filter (SF) gate. However, how these cues cause conformational changes in the SF of some K2P channels remains unclear. Herein, we investigate the mechanisms by which extracellular pH affects gating in an alkaline-activated K2P channel, TALK1, using electrophysiology and molecular dynamics (MD) simulations. We show that R233, located at the N-terminal end of transmembrane segment 4, is the primary pHo sensor. This residue distally regulates the orientation of the carbonyl group at the S1 potassium-binding site through an interacting network composed of residues on transmembrane segment 4, the pore helix domain 1, and the SF. Moreover, in the presence of divalent cations, we found the acidic pH-activated R233E mutant recapitulates the network interactions of protonated R233. Intriguingly, our data further suggested stochastic coupling between R233 and the SF gate, which can be described by an allosteric gating model. We propose that this allosteric model could predict the hybrid pH sensitivity in heterodimeric channels with alkaline-activated and acidic-activated K2P subunits. |
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| Keywords: | potassium channel, molecular dynamics, molecular modeling, structural model, K2P, TALK1, pH sensing, C-type gate, channel activation |
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| Publication status: | Published |
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| Publication version: | Version of Record |
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| Submitted for review: | 19.04.2022 |
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| Article acceptance date: | 24.12.2021 |
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| Publication date: | 29.04.2022 |
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| Publisher: | ASBMB |
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| Year of publishing: | 2022 |
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| Number of pages: | str. 1-13 |
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| Numbering: | Letn. 298, št. 6, št. članka 101998 |
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| PID: | 20.500.12556/DKUM-98729  |
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| UDC: | 612 |
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| ISSN on article: | 1083-351X |
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| COBISS.SI-ID: | 283339523 |
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| DOI: | 10.1016/j.jbc.2022.101998 External Link |
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| Publication date in DKUM: | 03.07.2026 |
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| Views: | 287 |
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| Downloads: | 5 |
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| Metadata: |    |
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| Categories: | Misc.
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