Structural heterogeneity of the ion and lipid channel TMEM16F.

Simone Pifferi, Anna Menini, Vincent Torre, Nicola Galvanetto, Horst Vogel, Leonardo Puppulin, Zhongjie Ye, Holger Flechsig, Melanie Arndt, Cesar Adolfo Sánchez Triviño, Michael Di Palma, Shifeng Guo, Clemens M Franz, Arin Marchesi

Journal: Nature communications 2024;15(1):110

PMID: 38167485

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Abstract

Transmembrane protein 16 F (TMEM16F) is a Ca-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 Ca-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 Ca 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.

Address: International School for Advanced Studies (SISSA), 34136, Trieste, Italy.; Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, 518055, Shenzhen, China.; Department of Physics, University of Zurich, 8057, Zurich, Switzerland.; Department of Biochemistry, University of Zurich, 8057, Zurich, Switzerland.; Department of Molecular Sciences and Nanosystems, Ca' Foscari University of Venice, I-30172 Mestre, Venice, Italy.; WPI Nano Life Science Institute, Kanazawa University, Kakuma-machi, 920-1192, Kanazawa, Japan.; International School for Advanced Studies (SISSA), 34136, Trieste, Italy.; Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, 60126, Ancona, Italy.; WPI Nano Life Science Institute, Kanazawa University, Kakuma-machi, 920-1192, Kanazawa, Japan.; Department of Biochemistry, University of Zurich, 8057, Zurich, Switzerland.; International School for Advanced Studies (SISSA), 34136, Trieste, Italy.; Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, 60126, Ancona, Italy.; Shenzhen Key Laboratory of Smart Sensing and Intelligent Systems, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.; Guangdong Provincial Key Lab of Robotics and Intelligent System, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.; Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, 518055, Shenzhen, China.; Institut des Sciences et Ingénierie Chimiques (ISIC), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.; International School for Advanced Studies (SISSA), 34136, Trieste, Italy. [email protected].; Institute of Materials (ION-CNR), Area Science Park, Basovizza, 34149, Trieste, Italy. [email protected].; BIoValley Investments System and Solutions (BISS), 34148, Trieste, Italy. [email protected].; WPI Nano Life Science Institute, Kanazawa University, Kakuma-machi, 920-1192, Kanazawa, Japan. [email protected].; Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, 60126, Ancona, Italy. [email protected].

DOI: 10.1038/s41467-023-44377-7

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MeSH Terms: Anoctamins, Ion Channels, Electrophysiological Phenomena, Phospholipid Transfer Proteins, Lipids, Calcium