8B8M

Cryo-EM structure of Ca2+-bound mTMEM16F N562A mutant in Digitonin open/closed

Summary for 8B8M

• Entry DOI: 10.2210/pdb8b8m/pdb
• EMDB information: 15917
• Descriptor: Anoctamin-6, CALCIUM ION (2 entities in total)
• Functional Keywords: membrane protein, lipid transport, lipid scramblase, ion channel, blood coagulation, membrane fusion
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 2
• Total formula weight: 227081.67

Authors

Arndt, M.,Alvadia, C.,Straub, M.S.,Clerico-Mosina, V.,Paulino, C.,Dutzler, R. (deposition date: 2022-10-04, release date: 2022-11-16, Last modification date: 2024-11-06)

Primary citation

Arndt, M.,Alvadia, C.,Straub, M.S.,Clerico Mosina, V.,Paulino, C.,Dutzler, R.
Structural basis for the activation of the lipid scramblase TMEM16F.
Nat Commun, 13:6692-6692, 2022

PubMed 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 Ca. 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.

PubMed: 36335104
DOI: 10.1038/s41467-022-34497-x

Experimental method

ELECTRON MICROSCOPY (3.49 Å)