Structural basis for the activation of the lipid scramblase TMEM16F

• DOI: 10.1038/s41467-022-34497-x
• Publication Date: 2022-11-05T15:04:54Z
• Authors: Melanie Arndt; Carolina Alvadia; Monique S. Straub; Vanessa Clerico M...; Cristina Paulino; Raimund Dutzler
• Keywords: 0301 basic medicine; 1000 Multidisciplinary; 0303 health sciences; Calcium/metabolism; Protein Conformation; Science; Q; Cryoelectron Microscopy; Anoctamins; 610 Medicine & health; 1600 General Chemistry; Anoctamins/genetics; Lipids; 3100 General Physics and Astronomy; Article; 03 medical and health sciences; 1300 General Biochemistry, Genetics and Molecular Biology; 10019 Department of Biochemistry; 570 Life sciences; biology; Calcium; Phospholipid Transfer Proteins/metabolism; Phospholipid Transfer Proteins

AbstractTMEM16F, 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.