8A6I

Structure of the low complexity domain of TDP-43 (fragment 309-350) with methionine sulfoxide modifications

Summary for 8A6I

• Entry DOI: 10.2210/pdb8a6i/pdb
• NMR Information: BMRB: 34737
• Descriptor: TAR DNA-binding protein 43 (1 entity in total)
• Functional Keywords: tdp-43, low complexity domain, prion-like domain, methionine sulfoxide, llps, unknown function
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 4331.80

Authors

Carrasco, J.,Anton, R.,Pantoja-Uceda, D.,Laurents, D.V.,Oroz, J. (deposition date: 2022-06-17, release date: 2023-02-08, Last modification date: 2024-10-23)

Primary citation

Carrasco, J.,Anton, R.,Valbuena, A.,Pantoja-Uceda, D.,Mukhi, M.,Hervas, R.,Laurents, D.V.,Gasset, M.,Oroz, J.
Metamorphism in TDP-43 prion-like domain determines chaperone recognition.
Nat Commun, 14:466-466, 2023

PubMed 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.

PubMed: 36709343
DOI: 10.1038/s41467-023-36023-z

Experimental method

SOLUTION NMR