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bioRxiv · 10.1101/2022.11.15.516569

A canonical chaperone and a heat-resistant obscure (Hero) protein mediate similar conformational modulation and aggregation suppression of TDP-43

Lam, A. Y. W.·Tsuboyama, K.·Tadakuma, H.·Tomari, Y.
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Abstract

Protein misfolding and aggregation are characteristic features of neurodegenerative diseases. While molecular chaperones are well-known suppressors of these aberrant events, we recently reported that highly disordered, hydrophilic and charged heat-resistant obscure (Hero) proteins may have similar effects. Specifically, Hero proteins can maintain the activity of other proteins from denaturing conditions in vitro, while their overexpression can suppress cellular aggregation and toxicity associated with aggregation-prone proteins. However, it is unclear how these protective effects are achieved. Here, we utilized single-molecule FRET to monitor the conformations of the aggregation-prone prion-like low complexity domain (LCD) of TAR DNA-binding protein 43 (TDP-43). While we observed high conformational heterogeneity in wild-type LCD, the ALS-associated mutation A315T promoted collapsed conformations. In contrast, an Hsp40 chaperone, DNAJA2, and a Hero protein, Hero11 stabilized extended states of the LCD, consistent with their ability to suppress the aggregation of TDP-43. Our results link single-molecule effects on conformation to macro effects on bulk aggregation, where a Hero protein, like a chaperone, can maintain the conformational integrity of a client protein to prevent its aggregation.

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Lam, A. Y. W., Tsuboyama, K., Tadakuma, H., Tomari, Y.. 2022-11-15. A canonical chaperone and a heat-resistant obscure (Hero) protein mediate similar conformational modulation and aggregation suppression of TDP-43. https://doi.org/10.1101/2022.11.15.516569

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