Data from: Interactions between TTYH2 and APOE facilitate endosomal lipid transfer

Abstract The Tweety homologues (TTYHs) constitute a family of
eukaryotic membrane proteins that, on the basis of structural features,
were recently proposed to contribute to lipid transfer between soluble
carriers and cellular membranes1. However, in the absence of supporting
data, this function was hypothetical. Here through pull-down of endogenous
proteins, we identify APOE as the interaction partner of human TTYH2.
Subcellular fractionation and immunocytochemistry assays showed that both
proteins colocalize in endosomal compartments. Characterization of the
specific interaction between APOE and TTYH2 through binding assays and
structural studies enabled us to identify an epitope in an extended domain
of TTYH2 that faces the endosomal lumen. Structures of complexes with
APOE-containing lipoprotein particles revealed a binding mode that places
lipids in a suitable position to facilitate their diffusion into the
membrane. Moreover, in vitro studies revealed that lipid transfer is
accelerated by TTYH2. Collectively, our findings indicate that TTYH2 has a
role in the unloading of APOE-containing lipoproteins after they are
endocytosed. These results define a new protein class that facilitates the
extraction of lipids from and their insertion into cellular membranes.
Although ubiquitous, this process could be of particular relevance in the
brain, where APOE is involved in the transfer of lipids between astrocytes
and neurons.