Structure of human PIEZO1 and its slow-inactivating channelopathy mutants
PIEZO channels transmit mechanical force signals to cells, allowing them to make critical decisions during development and in pathophysiological conditions. Their fast/slow inactivation modes have been implicated in mechanopathologies but remain poorly understood. Here, we report several near-atomic...
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eLife Sciences Publications Ltd
2025-07-01
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| Online Access: | https://elifesciences.org/articles/101923 |
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| author | Yuanyue Shan Xinyi Guo Mengmeng Zhang Meiyu Chen Ying Li Mingfeng Zhang Duanqing Pei |
| author_facet | Yuanyue Shan Xinyi Guo Mengmeng Zhang Meiyu Chen Ying Li Mingfeng Zhang Duanqing Pei |
| author_sort | Yuanyue Shan |
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| description | PIEZO channels transmit mechanical force signals to cells, allowing them to make critical decisions during development and in pathophysiological conditions. Their fast/slow inactivation modes have been implicated in mechanopathologies but remain poorly understood. Here, we report several near-atomic resolution cryo-EM structures of fast-inactivating wild-type human PIEZO1 (hPIEZO1) and its slow-inactivating channelopathy mutants with or without its auxiliary subunit MDFIC. Our results suggest that hPIEZO1 has a more flattened and extended architecture than curved mouse PIEZO1 (mPIEZO1). The multi-lipidated MDFIC subunits insert laterally into the hPIEZO1 pore module like mPIEZO1, resulting in a more curved and extended state. Interestingly, the high-resolution structures suggest that the pore lipids, which directly seal the central hydrophobic pore, may be involved in the rapid inactivation of hPIEZO1. While the severe hereditary erythrocytosis mutant R2456H significantly slows down the inactivation of hPIEZO1, the hPIEZO1-R2456H-MDFIC complex shows a more curved and contracted structure with an inner helix twist due to the broken link between the pore lipid and R2456H. These results suggest that the pore lipids may be involved in the mechanopathological rapid inactivation mechanism of PIEZO channels. |
| format | Article |
| id | doaj-art-784ac596894c4cafaaf53d25a23e55b0 |
| institution | DOAJ |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | eLife Sciences Publications Ltd |
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| spelling | doaj-art-784ac596894c4cafaaf53d25a23e55b02025-08-20T02:40:27ZengeLife Sciences Publications LtdeLife2050-084X2025-07-011310.7554/eLife.101923Structure of human PIEZO1 and its slow-inactivating channelopathy mutantsYuanyue Shan0https://orcid.org/0000-0001-6291-2433Xinyi Guo1Mengmeng Zhang2Meiyu Chen3Ying Li4Mingfeng Zhang5https://orcid.org/0000-0002-0138-3934Duanqing Pei6https://orcid.org/0000-0002-5222-014XLaboratory of Cell Fate Control, School of Life Sciences, Westlake University, Hangzhou, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, ChinaLaboratory of Cell Fate Control, School of Life Sciences, Westlake University, Hangzhou, ChinaLaboratory of Cell Fate Control, School of Life Sciences, Westlake University, Hangzhou, ChinaLaboratory of Cell Fate Control, School of Life Sciences, Westlake University, Hangzhou, ChinaLaboratory of Cell Fate Control, School of Life Sciences, Westlake University, Hangzhou, ChinaLaboratory of Cell Fate Control, School of Life Sciences, Westlake University, Hangzhou, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China; Fudan University, Shanghai, ChinaLaboratory of Cell Fate Control, School of Life Sciences, Westlake University, Hangzhou, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, ChinaPIEZO channels transmit mechanical force signals to cells, allowing them to make critical decisions during development and in pathophysiological conditions. Their fast/slow inactivation modes have been implicated in mechanopathologies but remain poorly understood. Here, we report several near-atomic resolution cryo-EM structures of fast-inactivating wild-type human PIEZO1 (hPIEZO1) and its slow-inactivating channelopathy mutants with or without its auxiliary subunit MDFIC. Our results suggest that hPIEZO1 has a more flattened and extended architecture than curved mouse PIEZO1 (mPIEZO1). The multi-lipidated MDFIC subunits insert laterally into the hPIEZO1 pore module like mPIEZO1, resulting in a more curved and extended state. Interestingly, the high-resolution structures suggest that the pore lipids, which directly seal the central hydrophobic pore, may be involved in the rapid inactivation of hPIEZO1. While the severe hereditary erythrocytosis mutant R2456H significantly slows down the inactivation of hPIEZO1, the hPIEZO1-R2456H-MDFIC complex shows a more curved and contracted structure with an inner helix twist due to the broken link between the pore lipid and R2456H. These results suggest that the pore lipids may be involved in the mechanopathological rapid inactivation mechanism of PIEZO channels.https://elifesciences.org/articles/101923cryo-EMPIEZOmembrane channels |
| spellingShingle | Yuanyue Shan Xinyi Guo Mengmeng Zhang Meiyu Chen Ying Li Mingfeng Zhang Duanqing Pei Structure of human PIEZO1 and its slow-inactivating channelopathy mutants eLife cryo-EM PIEZO membrane channels |
| title | Structure of human PIEZO1 and its slow-inactivating channelopathy mutants |
| title_full | Structure of human PIEZO1 and its slow-inactivating channelopathy mutants |
| title_fullStr | Structure of human PIEZO1 and its slow-inactivating channelopathy mutants |
| title_full_unstemmed | Structure of human PIEZO1 and its slow-inactivating channelopathy mutants |
| title_short | Structure of human PIEZO1 and its slow-inactivating channelopathy mutants |
| title_sort | structure of human piezo1 and its slow inactivating channelopathy mutants |
| topic | cryo-EM PIEZO membrane channels |
| url | https://elifesciences.org/articles/101923 |
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