Structural basis for the activation of the lipid scramblase TMEM16F

Nat Commun. 2022 Nov 5;13(1):6692. doi: 10.1038/s41467-022-34497-x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anoctamins* / genetics
  • Anoctamins* / metabolism
  • Calcium / metabolism
  • Cryoelectron Microscopy
  • Lipids
  • Phospholipid Transfer Proteins* / metabolism
  • Protein Conformation


  • Anoctamins
  • Phospholipid Transfer Proteins
  • Lipids
  • Calcium