78: Unloading Lipids: TTYH2 Meets APOE

Sukalskaia A et al., Nature - This Nature study identifies APOE as an interaction partner of human TTYH2, maps their endosomal colocalization and binding site by cryo-EM, and shows that TTYH2 accelerates lipid transfer from APOE-containing lipoproteins to membranes in vitro. Key terms: TTYH2, APOE, lipid transfer, endosomes, cryo-EM. Study Highlights:Using sybody pull-downs and mass spectrometry the authors identified APOE as a TTYH2 interaction partner and showed both proteins colocalize in endosomal fractions and by confocal microscopy. Single-molecule force spectroscopy and competitive sybody displacement localized the APOE-binding site to the extracellular tip of TTYH2. Cryo-EM of complexes and lipoprotein discs positioned APOE and lipids near a hydrophobic cavity that links the membrane and lumen, and high-resolution maps revealed a continuous lipid path into the cavity. In DPPC-enriched proteoliposomes, TTYH2 markedly accelerated transfer of fluorescent lipids from APOE-containing particles while no convincing scramblase activity was detected. Conclusion:TTYH2 binds APOE in endosomal compartments and functions as a paralogue-specific facilitator that brings lipids from APOE-containing lipoproteins into the membrane via a hydrophobic extracellular cavity; further cellular studies are needed to define physiological and pathological roles. Music:Enjoy the music based on this article at the end of the episode. Article title:Interactions between TTYH2 and APOE facilitate endosomal lipid transfer First author:Sukalskaia A Journal:Nature DOI:10.1038/s41586-025-09200-x Reference:Sukalskaia A., Karner A., Pugnetti A., Weber F., Plochberger B. & Dutzler R. Interactions between TTYH2 and APOE facilitate endosomal lipid transfer. Nature. doi:10.1038/s41586-025-09200-x (2025). 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/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/ttyh2-apoe-endosomal-lipid-transfer QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-07-17. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript's portrayal of the primary mechanistic claims and experimental evidence from the Nature article, including interaction evidence, endosomal localization, binding site, structural interpretation, lipoprotein-disc binding, lipid transfer kinetics, scramblase tests, and brain relevance.- transcript topics: APOE–TTYH2 interaction and pull-down evidence; Endosomal colocalization of APOE and TTYH2; Extracellular tip epitope binding and cryo-EM mapping; APOE-containing lipoprotein discs and lipids near the hydrophobic cavity; Single-molecule force spectroscopy (SMFS) and koff measurements; In vitro lipid-transfer assays and DPPC liposome results QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 7- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi- article_title- article_journal- license Factual Items Audited:- APOE identified as interaction partner of TTYH2; both proteins colocalize in endosomes- TTYH2–APOE interactions observed across lipidation states; extracellu...