Structural basis for the activation of the lipid scramblase TMEM16F
| Autor: | Arndt, Melanie, Alvadia, Carolina, Straub, Monique S, Clerico Mosina, Vanessa, Paulino, Cristina, Dutzler, Raimund |
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| Přispěvatelé: | University of Zurich, Dutzler, Raimund, Electron Microscopy |
| Rok vydání: | 2022 |
| Předmět: |
1000 Multidisciplinary
Calcium/metabolism Multidisciplinary Protein Conformation Cryoelectron Microscopy Anoctamins General Physics and Astronomy 610 Medicine & health 1600 General Chemistry General Chemistry Anoctamins/genetics Lipids 3100 General Physics and Astronomy General Biochemistry Genetics and Molecular Biology 1300 General Biochemistry Genetics and Molecular Biology 10019 Department of Biochemistry 570 Life sciences biology Calcium Phospholipid Transfer Proteins/metabolism Phospholipid Transfer Proteins |
| Zdroj: | Nature Communications, 13(1):6692. Nature Publishing Group |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-022-34497-x |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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