Fig. 1.

Protein disaggregases and bait RNAs to counter aberrant protein states. (A) Native proteins (left) can transition to pathological states, which can present initially as liquid–liquid phase-separated condensates (top) or as ordered amyloids (right). To prevent and reverse these disease-causing processes, researchers are working to understand how protein disaggregases can be harnessed against diseases that remain incurable. (B-D) Three protein-disaggregase systems, Hsp104 [B; Protein Data Bank (PDB) 5VJH and 5VYA]; Hsp110, Hsp70 (PDB 2KHO) and Hsp40 (C); and Skd3 (D) all use ATP hydrolysis to power protein disaggregation. (E) Kapβ2 (PDB 4FDD) is a nuclear-import receptor that acts as a disaggregase in an ATP-independent manner. (F) TRIM family proteins, including TRIM11 and TRIM19, also act as ATP-independent disaggregases in concert with the proteosome to degrade aberrant proteins. (G) Bait RNAs such as Clip_34nt can also act as chaperones by preventing aberrant phase transitions of TDP-43.