A liposome assay showing the absence of scrambling in TTYH proteins and a lipidomics analysis of TTYH2

The Tweety homologues (TTYHs) are members of a conserved family of
eukaryotic membrane proteins that are abundant in the brain. The three
human paralogs were assigned to function as anion channels that are either
activated by Ca2+ or cell swelling. To uncover their unknown architecture
and its relationship to function, we have determined the structures of
human TTYH1–3 by cryo-electron microscopy. All structures display
equivalent features of a dimeric membrane protein that contains five
transmembrane segments and an extended extracellular domain.  As
none of the proteins shows features reminiscent of an anion channel, we
revisited functional experiments and did not find any indication of ion
conduction. Instead, we find density in an extended hydrophobic pocket
contained in the extracellular domain that emerges from the lipid bilayer,
which suggests a role of TTYH proteins in the interaction with lipid-like
compounds residing in the membrane.