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Título: | Metamorphism in TDP-43 prion-like domain determines chaperone recognition |
Autor: | Carrasco, Jaime CSIC ORCID; Antón, Rosa CSIC; Valbuena, Alejandro CSIC ORCID; Pantoja-Uceda, D.; Mukhi, Mayur; Hervás, Rubén CSIC ORCID; Laurents, Douglas V. CSIC ORCID ; Gasset, M. CSIC ORCID; Oroz, Javier CSIC ORCID | Fecha de publicación: | 28-ene-2023 | Editor: | Nature Publishing Group | Citación: | Nature Communications 14: 466 (2023) | Resumen: | The RNA binding protein TDP-43 forms cytoplasmic inclusions via its C-terminal prion-like domain in several neurodegenerative diseases. Aberrant TDP-43 aggregation arises upon phase de-mixing and transitions from liquid to solid states, following still unknown structural conversions which are primed by oxidative stress and chaperone inhibition. Despite the well-established protective roles for molecular chaperones against protein aggregation pathologies, knowledge on the determinants of chaperone recognition in disease-related prions is scarce. Here we show that chaperones and co-chaperones primarily recognize the structured elements in TDP-43´s prion-like domain. Significantly, while HSP70 and HSP90 chaperones promote TDP-43 phase separation, co-chaperones from the three classes of the large human HSP40 family (namely DNAJA2, DNAJB1, DNAJB4 and DNAJC7) show strikingly different effects on TDP-43 de-mixing. Dismantling of the second helical element in TDP-43 prion-like domain by methionine sulfoxidation impacts phase separation and amyloid formation, abrogates chaperone recognition and alters phosphorylation by casein kinase-1δ. Our results show that metamorphism in the post-translationally modified TDP-43 prion-like domain encodes determinants that command mechanisms with major relevance in disease. | Descripción: | 15 pags., 6 figs. | Versión del editor: | https://doi.org/10.1038/s41467-023-36023-z | URI: | http://hdl.handle.net/10261/330425 | DOI: | 10.1038/s41467-023-36023-z | E-ISSN: | 2041-1723 |
Aparece en las colecciones: | (IQF) Artículos |
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Fichero | Descripción | Tamaño | Formato | |
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Metamorphism in TDP-43.pdf | Artículo principal | 3,98 MB | Adobe PDF | Visualizar/Abrir |
Supplementary information (1).docx | Supplementary information | 4,79 MB | Microsoft Word XML | Visualizar/Abrir |
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