Structural heterogeneity of the ion and lipid channel TMEM16F

Zhongjie Ye, Nicola Galvanetto, Leonardo Puppulin, Simone Pifferi, Holger Flechsig, Melanie Arndt, Cesar Adolfo Sánchez Triviño, Michael Palma, Shifeng Guo, Horst Vogel, Anna Menini, Clemens M. Franz, Vincent Torre () and Arin Marchesi ()
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Zhongjie Ye: International School for Advanced Studies (SISSA)
Nicola Galvanetto: University of Zurich
Leonardo Puppulin: Ca’ Foscari University of Venice
Simone Pifferi: International School for Advanced Studies (SISSA)
Holger Flechsig: Kanazawa University, Kakuma-machi
Melanie Arndt: University of Zurich
Cesar Adolfo Sánchez Triviño: International School for Advanced Studies (SISSA)
Michael Palma: Università Politecnica delle Marche
Shifeng Guo: Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences
Horst Vogel: Chinese Academy of Sciences
Anna Menini: International School for Advanced Studies (SISSA)
Clemens M. Franz: Kanazawa University, Kakuma-machi
Vincent Torre: International School for Advanced Studies (SISSA)
Arin Marchesi: Kanazawa University, Kakuma-machi

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-023-44377-7

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