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| Title | Interactions between TTYH2 and APOE facilitate endosomal lipid transfer. |
|---|---|
| Journal, issue, pages | Nature, Vol. 644, Issue 8075, Page 273-279, Year 2025 |
| Publish date | Jun 25, 2025 |
 Authors | Anastasiia Sukalskaia / Andreas Karner / Anna Pugnetti / Florian Weber / Birgit Plochberger / Raimund Dutzler /   |
| PubMed 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 ...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 membranes. 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. |
 External links | Nature / PubMed:40562935 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 2.74 - 15.0 Å |
| Structure data | EMDB-51106, PDB-9g6x: EMDB-51108, PDB-9g71: EMDB-53249, PDB-9qnr:  EMDB-53251: TTYH2 in complex with lipidated ApoE, dataset1 map1  EMDB-53267: Cryo-EM structure of TTYH3 in GDN after incubation with ApoE, map1  EMDB-53269: TTYH2 in complex with lipidated ApoE, dataset1 map2  EMDB-53271: ApoE lipoprotein disc, map3  EMDB-53272: ApoE lipoprotein disc, map1  EMDB-53273: ApoE lipoprotein disc, map2  EMDB-53280: TTYH2 in complex with lipidated ApoE, dataset2  EMDB-53289: TTYH2 in complex with delipidated ApoE  EMDB-53290: TTYH2 in complex with sybody 2 in GDN  EMDB-53291: TTYH2 in complex with sybody 1 in cell-derived vesicles  EMDB-53292: TTYH2 in complex with lipidated ApoE in cell-derived vesicles  EMDB-53293: TTYH2 in complex with C-terminal fragment of ApoE  EMDB-53297: TTYH2 in complex with ApoE coexpressed, dataset1 map2  EMDB-53301: TTYH2 in complex with ApoE coexpressed, dataset1 map1  EMDB-53302: TTYH2 in complex with ApoE coexpressed, dataset2 map2  EMDB-53303: TTYH2 in complex with ApoE coexpressed, dataset2 map1  EMDB-53304: TTYH2 in complex with ApoE coexpressed, dataset 3 |
| Chemicals |  ChemComp-NAG:  ChemComp-PLC:  ChemComp-CLR:  ChemComp-CPL: |
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 Keywords | MEMBRANE PROTEIN / complex / sybody / nanobody / TTYH2 / lipid interactions |
vicugna pacos (alpaca)
homo sapiens (human)