Molecular mechanism underlying desensitization of the proton-activated chloride channel PAC
Desensitization is a common property of membrane receptors, including ion channels. The newly identified proton-activated chloride (PAC) channel plays an important role in regulating the pH and size of organelles in the endocytic pathway, and is also involved in acid-induced cell death. However, how...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-12-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/82955 |
| _version_ | 1797979124378107904 |
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| author | James Osei-Owusu Zheng Ruan Ljubica Mihaljević Daniel S Matasic Kevin Hong Chen Wei Lü Zhaozhu Qiu |
| author_facet | James Osei-Owusu Zheng Ruan Ljubica Mihaljević Daniel S Matasic Kevin Hong Chen Wei Lü Zhaozhu Qiu |
| author_sort | James Osei-Owusu |
| collection | DOAJ |
| description | Desensitization is a common property of membrane receptors, including ion channels. The newly identified proton-activated chloride (PAC) channel plays an important role in regulating the pH and size of organelles in the endocytic pathway, and is also involved in acid-induced cell death. However, how the PAC channel desensitizes is largely unknown. Here, we show by patch-clamp electrophysiological studies that PAC (also known as TMEM206/ASOR) undergoes pH-dependent desensitization upon prolonged acid exposure. Through structure-guided and comprehensive mutagenesis, we identified several residues critical for PAC desensitization, including histidine (H) 98, glutamic acid (E) 94, and aspartic acid (D) 91 at the extracellular extension of the transmembrane helix 1 (TM1), as well as E107, D109, and E250 at the extracellular domain (ECD)–transmembrane domain (TMD) interface. Structural analysis and molecular dynamic simulations revealed extensive interactions between residues at the TM1 extension and those at the ECD–TMD interface. These interactions likely facilitate PAC desensitization by stabilizing the desensitized conformation of TM1, which undergoes a characteristic rotational movement from the resting and activated states to the desensitized state. Our studies establish a new paradigm of channel desensitization in this ubiquitously expressed ion channel and pave the way for future investigation of its relevance in cellular physiology and disease. |
| first_indexed | 2024-04-11T05:34:04Z |
| format | Article |
| id | doaj.art-b71011fe8a844ef9b81177660edfc2f7 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T05:34:04Z |
| publishDate | 2022-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-b71011fe8a844ef9b81177660edfc2f72022-12-22T15:39:07ZengeLife Sciences Publications LtdeLife2050-084X2022-12-011110.7554/eLife.82955Molecular mechanism underlying desensitization of the proton-activated chloride channel PACJames Osei-Owusu0https://orcid.org/0000-0002-8676-4444Zheng Ruan1https://orcid.org/0000-0002-4412-4916Ljubica Mihaljević2Daniel S Matasic3Kevin Hong Chen4Wei Lü5https://orcid.org/0000-0002-3009-1025Zhaozhu Qiu6https://orcid.org/0000-0002-9122-6077Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, United StatesDepartment of Structural Biology, Van Andel Institute, Grand Rapids, United StatesDepartment of Physiology, Johns Hopkins University School of Medicine, Baltimore, United StatesDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, United StatesDepartment of Physiology, Johns Hopkins University School of Medicine, Baltimore, United StatesDepartment of Structural Biology, Van Andel Institute, Grand Rapids, United StatesDepartment of Physiology, Johns Hopkins University School of Medicine, Baltimore, United States; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United StatesDesensitization is a common property of membrane receptors, including ion channels. The newly identified proton-activated chloride (PAC) channel plays an important role in regulating the pH and size of organelles in the endocytic pathway, and is also involved in acid-induced cell death. However, how the PAC channel desensitizes is largely unknown. Here, we show by patch-clamp electrophysiological studies that PAC (also known as TMEM206/ASOR) undergoes pH-dependent desensitization upon prolonged acid exposure. Through structure-guided and comprehensive mutagenesis, we identified several residues critical for PAC desensitization, including histidine (H) 98, glutamic acid (E) 94, and aspartic acid (D) 91 at the extracellular extension of the transmembrane helix 1 (TM1), as well as E107, D109, and E250 at the extracellular domain (ECD)–transmembrane domain (TMD) interface. Structural analysis and molecular dynamic simulations revealed extensive interactions between residues at the TM1 extension and those at the ECD–TMD interface. These interactions likely facilitate PAC desensitization by stabilizing the desensitized conformation of TM1, which undergoes a characteristic rotational movement from the resting and activated states to the desensitized state. Our studies establish a new paradigm of channel desensitization in this ubiquitously expressed ion channel and pave the way for future investigation of its relevance in cellular physiology and disease.https://elifesciences.org/articles/82955chloride channeldesensitizationinactivationPACTMEM206ASOR |
| spellingShingle | James Osei-Owusu Zheng Ruan Ljubica Mihaljević Daniel S Matasic Kevin Hong Chen Wei Lü Zhaozhu Qiu Molecular mechanism underlying desensitization of the proton-activated chloride channel PAC eLife chloride channel desensitization inactivation PAC TMEM206 ASOR |
| title | Molecular mechanism underlying desensitization of the proton-activated chloride channel PAC |
| title_full | Molecular mechanism underlying desensitization of the proton-activated chloride channel PAC |
| title_fullStr | Molecular mechanism underlying desensitization of the proton-activated chloride channel PAC |
| title_full_unstemmed | Molecular mechanism underlying desensitization of the proton-activated chloride channel PAC |
| title_short | Molecular mechanism underlying desensitization of the proton-activated chloride channel PAC |
| title_sort | molecular mechanism underlying desensitization of the proton activated chloride channel pac |
| topic | chloride channel desensitization inactivation PAC TMEM206 ASOR |
| url | https://elifesciences.org/articles/82955 |
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