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Interactions between TTYH2 and APOE facilitate endosomal lipid transfer
Anastasiia Sukalskaia1, Andreas Karner2, Anna Pugnetti1
1Department of Biochemistry University of Zurich, Zurich, Switzerland.
Nature
|June 25, 2025
Summary
The Tweety homologue TTYH2 protein interacts with APOE to facilitate lipid transfer from lipoproteins into cells. This discovery reveals a new mechanism for membrane lipid extraction, particularly relevant in the brain.
Area of Science:
- Biochemistry
- Cell Biology
- Structural Biology
Background:
- Tweety homologues (TTYHs) are eukaryotic membrane proteins with a proposed but unproven role in lipid transfer.
- The specific function of TTYH2 in lipid transport remained hypothetical due to a lack of experimental evidence.
Purpose of the Study:
- To investigate the function of TTYH2 in lipid transfer.
- To identify interaction partners of TTYH2 and elucidate its mechanism of action.
Main Methods:
- Endogenous protein pull-down assays to identify TTYH2 interaction partners.
- Subcellular fractionation and immunocytochemistry to determine protein localization.
- Binding assays and structural studies (including complex structures) to characterize the APOE-TTYH2 interaction.
- In vitro lipid transfer assays.
Main Results:
- APOE was identified as the interaction partner of human TTYH2.
- TTYH2 and APOE colocalize in endosomal compartments.
- Structural studies revealed how TTYH2 binds APOE-containing lipoproteins, positioning lipids for membrane diffusion.
- TTYH2 was shown to accelerate lipid transfer in vitro.
- TTYH2 facilitates the unloading of endocytosed APOE-containing lipoproteins.
Conclusions:
- TTYH2 plays a crucial role in unloading lipids from APOE-containing lipoproteins after endocytosis.
- This study defines a novel class of proteins involved in membrane lipid extraction and insertion.
- The identified lipid transfer mechanism is significant for brain function, where APOE mediates lipid exchange between astrocytes and neurons.
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