Metamorphism in TDP-43 prion-like domain determines chaperone recognition
Entidad
UAM. Departamento de Biología MolecularEditor
Nature ResearchFecha de edición
2023-01-28Cita
10.1038/s41467-023-36023-z
Nature Communications 14.1 (2023): 466
ISSN
2041-1723 (online)DOI
10.1038/s41467-023-36023-zProyecto
Gobierno de España. SAF2016-76678-C2-2-RVersión del editor
https://doi.org/10.1038/s41467-023-36023-zMaterias
TDP-43; RNA; HSP70; HSP90; Biología y Biomedicina / BiologíaDerechos
© The Author(s) 2023Resumen
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 cochaperones primarily recognize the structured elements in TDP-43´s prionlike domain. Significantly, while HSP70 and HSP90 chaperones promote TDP43 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
Lista de ficheros
Google Scholar:Carrasco, Jaime
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Antón, Rosa
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Valbuena, Alejandro
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Pantoja-Uceda, David
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Mukhi, Mayur
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Hervás, Rubén
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Laurents, Douglas V.
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Gasset, María
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Oroz, Javier
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