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

Misfolding and aggregation of proteins are characteristic features in the progression of neurodegenerative diseases. While molecular chaperones are well-known suppressors of these aberrant events, we recently reported that a widespread family of heat-resistant obscure (Hero) proteins may also play a similar role. However, it is unclear how such electrostatically charged intrinsically disordered proteins protect client proteins from denaturation and aggregation. Here we utilize single-molecule FRET to monitor the conformations of an aggregation-prone protein, TDP-43. While we observed high conformational heterogeneity of wild-type TDP-43, the ALS-associated mutation A315T promoted collapsed conformations. In contrast, a canonical passive chaperone, DNAJA2, and a Hero protein, Hero11, both of which prevent TDP-43 aggregation in cells, promoted extended conformations. Our results link single-molecule effects on the TDP-43 conformation to macro effects on bulk aggregation propensity, where a Hero protein, like a canonical chaperone, maintains the conformational integrity of a client protein to prevent its aggregation.