️ Episode 78: Interactions between TTYH2 and APOE Facilitate Endosomal Lipid Transfer

In this episode of PaperCast Base by Base, we explore the discovery and characterization of the interaction between the membrane protein TTYH2 and apolipoprotein E (APOE), and how this partnership drives lipid transfer within endosomal compartments.

Study Highlights:

Pull-down assays and mass spectrometry identified APOE as a binding partner of human TTYH2 in endosomes, and subcellular fractionation confirmed their colocalization within endosomal fractions. Cryo-EM structures of TTYH2–APOE complexes revealed that APOE binds to an epitope on the extracellular domain of the TTYH2 dimer, positioning lipid cargo for membrane insertion. In vitro lipid-transfer assays demonstrated that TTYH2 accelerates the exchange of lipids between APOE-containing particles and lipid bilayers, with specificity absent in the TTYH3 paralogue. Force spectroscopy and competitive binding assays further mapped the interaction to the C-terminal domain of APOE, highlighting a mechanism distinct from classical receptor-mediated uptake.

Conclusion:

This work uncovers TTYH2 as a novel endosomal lipid-transfer catalyst that may play a critical role in neuronal lipid homeostasis and offers a new target for understanding lipid trafficking in health and disease.

Reference:

Sukalskaia A, Karner A, Pugnetti A, Weber F, Plochberger B & Dutzler R. (2025). Interactions between TTYH2 and APOE facilitate endosomal lipid transfer. Nature. https://doi.org/10.1038/s41586-025-09200-x

License:

This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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