Cryo-EM structures of the TTYH family reveal a novel architecture for lipid interactions

Abstract The Tweety homologs (TTYHs) are members of a conserved family eukaryotic membrane proteins that abundant in the brain. three human paralogs were assigned to function as anion channels either activated by Ca 2+ or cell swelling. To uncover their unknown architecture and its relationship function, we have determined structures TTYH1–3 cryo-electron microscopy. All display equivalent features dimeric protein contains five transmembrane segments an extended extracellular domain. As none shows attributes reminiscent channel, revisited functional experiments did not find any indication ion conduction. Instead, density hydrophobic pocket contained domain emerges from lipid bilayer, which suggests role TTYH interaction with lipid-like compounds residing membrane.