Journal
NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-34497-x
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Funding
- European Research Council (ERC) [339116]
- Center for Microscopy and Image Analysis (ZMB) of the University of Zurich
- Baugarten foundation
- Schwyzer-Winiker foundation
- Swiss National Science Foundation
- European Research Council (ERC) [339116] Funding Source: European Research Council (ERC)
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By studying the structure and function of TMEM16F mutants, the authors uncover how this protein is activated by an increase in intracellular Ca2+ to initiate blood coagulation and trophoblast fusion, providing valuable insights for drug target development.
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. TMEM16F is a dual ion channel and lipid scramblase that is involved in blood coagulation and cell fusion. Here, authors elucidate how the protein is activated by Ca2+ to accomplish both functions in a single protein conformation.
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