9O1Q

TMEM16F D409G mutant in liposomes in the presence of Ca2+ (active state)

Summary for 9O1Q

• Entry DOI: 10.2210/pdb9o1q/pdb
• EMDB information: 70017
• Descriptor: Anoctamin-6, CALCIUM ION (2 entities in total)
• Functional Keywords: membrane protein, lipid scramblase, tmem16, liposome, lipid transport
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 2
• Total formula weight: 212859.84

Authors

Feng, Z.,Accardi, A. (deposition date: 2025-04-03, release date: 2026-05-06, Last modification date: 2026-05-13)

Primary citation

Feng, Z.,Alvarenga, O.E.,Di Zanni, E.,Lee, S.,Khelashvili, G.,Accardi, A.
Calcium dependent activation of the TMEM16F scramblase and ion channel.
Nat.Struct.Mol.Biol., 33:664-676, 2026

PubMed Abstract: The ubiquitous transmembrane protein 16F (TMEM16F) Ca-activated channel and scramblase catalyzes phosphatidylserine externalization to enable blood coagulation, membrane fusion and brain immune surveillance. Despite its importance, the molecular mechanisms underlying TMEM16F activation remain poorly understood. Here, we obtained high-resolution cryo-electron microscopy structures of TMEM16F active in liposomes. In high-activity conditions, TMEM16F adopts two conformations, the canonical Ca-bound closed state and one where the upward rotation of the cytosolic domain leads to an X-shaped groove that forms a transmembrane pore and locally thins the membrane. Using mutagenesis, functional assays and molecular dynamics simulations, we show that the X-shaped groove is active and mediates nonselective ion flux and lipid scrambling through distinct pathways; ions move within the protein-delimited pore, whereas lipids skirt the X-shaped groove. Our findings provide a complete picture of TMEM16F Ca-dependent gating and demonstrate that imaging membrane proteins in a native-like environment can allow capturing otherwise inaccessible active states.

PubMed: 41998358
DOI: 10.1038/s41594-026-01789-5

Experimental method

ELECTRON MICROSCOPY (4.2 Å)