Structural heterogeneity of the ion and lipid channel TMEM16F
Abstract Transmembrane protein 16 F (TMEM16F) is a Ca2+-activated homodimer which functions as an ion channel and a phospholipid scramblase. Despite the availability of several TMEM16F cryogenic electron microscopy (cryo-EM) structures, the mechanism of activation and substrate translocation remains...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-44377-7 |
| _version_ | 1797363105359986688 |
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| author | Zhongjie Ye Nicola Galvanetto Leonardo Puppulin Simone Pifferi Holger Flechsig Melanie Arndt Cesar Adolfo Sánchez Triviño Michael Di Palma Shifeng Guo Horst Vogel Anna Menini Clemens M. Franz Vincent Torre Arin Marchesi |
| author_facet | Zhongjie Ye Nicola Galvanetto Leonardo Puppulin Simone Pifferi Holger Flechsig Melanie Arndt Cesar Adolfo Sánchez Triviño Michael Di Palma Shifeng Guo Horst Vogel Anna Menini Clemens M. Franz Vincent Torre Arin Marchesi |
| author_sort | Zhongjie Ye |
| collection | DOAJ |
| description | Abstract Transmembrane protein 16 F (TMEM16F) is a Ca2+-activated homodimer which functions as an ion channel and a phospholipid scramblase. Despite the availability of several TMEM16F cryogenic electron microscopy (cryo-EM) structures, the mechanism of activation and substrate translocation remains controversial, possibly due to restrictions in the accessible protein conformational space. In this study, we use atomic force microscopy under physiological conditions to reveal a range of structurally and mechanically diverse TMEM16F assemblies, characterized by variable inter-subunit dimerization interfaces and protomer orientations, which have escaped prior cryo-EM studies. Furthermore, we find that Ca2+-induced activation is associated to stepwise changes in the pore region that affect the mechanical properties of transmembrane helices TM3, TM4 and TM6. Our direct observation of membrane remodelling in response to Ca2+ binding along with additional electrophysiological analysis, relate this structural multiplicity of TMEM16F to lipid and ion permeation processes. These results thus demonstrate how conformational heterogeneity of TMEM16F directly contributes to its diverse physiological functions. |
| first_indexed | 2024-03-08T16:16:30Z |
| format | Article |
| id | doaj.art-9bd25adc2ffd46f18c51a341f17f0ddc |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-08T16:16:30Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-9bd25adc2ffd46f18c51a341f17f0ddc2024-01-07T12:35:04ZengNature PortfolioNature Communications2041-17232024-01-0115111510.1038/s41467-023-44377-7Structural heterogeneity of the ion and lipid channel TMEM16FZhongjie Ye0Nicola Galvanetto1Leonardo Puppulin2Simone Pifferi3Holger Flechsig4Melanie Arndt5Cesar Adolfo Sánchez Triviño6Michael Di Palma7Shifeng Guo8Horst Vogel9Anna Menini10Clemens M. Franz11Vincent Torre12Arin Marchesi13International School for Advanced Studies (SISSA)Department of Physics, University of ZurichDepartment of Molecular Sciences and Nanosystems, Ca’ Foscari University of VeniceInternational School for Advanced Studies (SISSA)WPI Nano Life Science Institute, Kanazawa University, Kakuma-machiDepartment of Biochemistry, University of ZurichInternational School for Advanced Studies (SISSA)Department of Experimental and Clinical Medicine, Università Politecnica delle MarcheShenzhen Key Laboratory of Smart Sensing and Intelligent Systems, Shenzhen Institute of Advanced Technology, Chinese Academy of SciencesShenzhen Institute of Advanced Technology, Chinese Academy of SciencesInternational School for Advanced Studies (SISSA)WPI Nano Life Science Institute, Kanazawa University, Kakuma-machiInternational School for Advanced Studies (SISSA)WPI Nano Life Science Institute, Kanazawa University, Kakuma-machiAbstract Transmembrane protein 16 F (TMEM16F) is a Ca2+-activated homodimer which functions as an ion channel and a phospholipid scramblase. Despite the availability of several TMEM16F cryogenic electron microscopy (cryo-EM) structures, the mechanism of activation and substrate translocation remains controversial, possibly due to restrictions in the accessible protein conformational space. In this study, we use atomic force microscopy under physiological conditions to reveal a range of structurally and mechanically diverse TMEM16F assemblies, characterized by variable inter-subunit dimerization interfaces and protomer orientations, which have escaped prior cryo-EM studies. Furthermore, we find that Ca2+-induced activation is associated to stepwise changes in the pore region that affect the mechanical properties of transmembrane helices TM3, TM4 and TM6. Our direct observation of membrane remodelling in response to Ca2+ binding along with additional electrophysiological analysis, relate this structural multiplicity of TMEM16F to lipid and ion permeation processes. These results thus demonstrate how conformational heterogeneity of TMEM16F directly contributes to its diverse physiological functions.https://doi.org/10.1038/s41467-023-44377-7 |
| spellingShingle | Zhongjie Ye Nicola Galvanetto Leonardo Puppulin Simone Pifferi Holger Flechsig Melanie Arndt Cesar Adolfo Sánchez Triviño Michael Di Palma Shifeng Guo Horst Vogel Anna Menini Clemens M. Franz Vincent Torre Arin Marchesi Structural heterogeneity of the ion and lipid channel TMEM16F Nature Communications |
| title | Structural heterogeneity of the ion and lipid channel TMEM16F |
| title_full | Structural heterogeneity of the ion and lipid channel TMEM16F |
| title_fullStr | Structural heterogeneity of the ion and lipid channel TMEM16F |
| title_full_unstemmed | Structural heterogeneity of the ion and lipid channel TMEM16F |
| title_short | Structural heterogeneity of the ion and lipid channel TMEM16F |
| title_sort | structural heterogeneity of the ion and lipid channel tmem16f |
| url | https://doi.org/10.1038/s41467-023-44377-7 |
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