Structural basis for the activation of the lipid scramblase TMEM16F

Melanie Arndt, Carolina Alvadia, Monique S. Straub, Vanessa Clerico Mosina, Cristina Paulino and Raimund Dutzler ()
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Melanie Arndt: Department of Biochemistry University of Zurich
Carolina Alvadia: Department of Biochemistry University of Zurich
Monique S. Straub: Department of Biochemistry University of Zurich
Vanessa Clerico Mosina: University of Groningen
Cristina Paulino: University of Groningen
Raimund Dutzler: Department of Biochemistry University of Zurich

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract TMEM16F, a member of the conserved TMEM16 family, plays a central role in the initiation of blood coagulation and the fusion of trophoblasts. The protein mediates passive ion and lipid transport in response to an increase in intracellular Ca2+. However, the mechanism of how the protein facilitates both processes has remained elusive. Here we investigate the basis for TMEM16F activation. In a screen of residues lining the proposed site of conduction, we identify mutants with strongly activating phenotype. Structures of these mutants determined herein by cryo-electron microscopy show major rearrangements leading to the exposure of hydrophilic patches to the membrane, whose distortion facilitates lipid diffusion. The concomitant opening of a pore promotes ion conduction in the same protein conformation. Our work has revealed a mechanism that is distinct for this branch of the family and that will aid the development of a specific pharmacology for a promising drug target.

Date: 2022
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DOI: 10.1038/s41467-022-34497-x

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