Metamorphism in TDP-43 prion-like domain determines chaperone recognition

Jaime Carrasco, Rosa Antón, Alejandro Valbuena, David Pantoja-Uceda, Mayur Mukhi, Rubén Hervás, Douglas V. Laurents, María Gasset and Javier Oroz ()
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Jaime Carrasco: Instituto de Química Física Rocasolano (IQFR), CSIC
Rosa Antón: Instituto de Química Física Rocasolano (IQFR), CSIC
Alejandro Valbuena: Universidad Autónoma de Madrid, Cantoblanco
David Pantoja-Uceda: Instituto de Química Física Rocasolano (IQFR), CSIC
Mayur Mukhi: University of Hong Kong
Rubén Hervás: University of Hong Kong
Douglas V. Laurents: Instituto de Química Física Rocasolano (IQFR), CSIC
María Gasset: Instituto de Química Física Rocasolano (IQFR), CSIC
Javier Oroz: Instituto de Química Física Rocasolano (IQFR), CSIC

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-36023-z

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