Structural basis of closed groove scrambling by a TMEM16 protein.

TitleStructural basis of closed groove scrambling by a TMEM16 protein.
Publication TypeJournal Article
Year of Publication2024
AuthorsFeng Z, Alvarenga OE, Accardi A
JournalNat Struct Mol Biol
Date Published2024 Apr 29

Activation of Ca2+-dependent TMEM16 scramblases induces phosphatidylserine externalization, a key step in multiple signaling processes. Current models suggest that the TMEM16s scramble lipids by deforming the membrane near a hydrophilic groove and that Ca2+ dependence arises from the different association of lipids with an open or closed groove. However, the molecular rearrangements underlying groove opening and how lipids reorganize outside the closed groove remain unknown. Here we directly visualize how lipids associate at the closed groove of Ca2+-bound fungal nhTMEM16 in nanodiscs using cryo-EM. Functional experiments pinpoint lipid-protein interaction sites critical for closed groove scrambling. Structural and functional analyses suggest groove opening entails the sequential appearance of two π-helical turns in the groove-lining TM6 helix and identify critical rearrangements. Finally, we show that the choice of scaffold protein and lipids affects the conformations of nhTMEM16 and their distribution, highlighting a key role of these factors in cryo-EM structure determination.

Alternate JournalNat Struct Mol Biol
PubMed ID38684930
PubMed Central ID10512157