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

15 pags., 6 figs.
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.
This work was supported by grants PID2019-109276RA-I00/AEI/ 10.13039/501100011033 (to J.O.), PID2019-103845RB-C21-AEI/10.13039/ 501100011033 (to M.G.) and SAF2016-76678-C2-2-R (MINECO/AEI/ FEDER UE to D.V.L.) from the Spanish AEI-Ministry of Science and Innovation and Enhanced New Staff Start-up Research Grant (The University of Hong Kong) to R.H. J.O. was a recipient of a Leonardo Grant from the Spanish BBVA Foundation (BBM_TRA_0203) and is a Ramón y Cajal Fellow of the Spanish AEI-Ministry of Science and Innovation (RYC2018-026042-I funded by MCIN/AEI/10.13039/501100011033 and by “ESF Investing in your future”). NMR experiments were performed in the “Manuel Rico” NMR Laboratory (LMR) of the Spanish National Research Council (CSIC), a node of the Spanish Large-Scale National Facility (ICTS R-LRB).