The metazoan protein disaggregase and amyloid depolymerase system: Hsp110, Hsp70, Hsp40, and small heat shock proteins

Abstract

A baffling aspect of metazoan proteostasis is the lack of an Hsp104 ortholog that rapidly disaggregates and reactivates misfolded polypeptides trapped in stress induced disordered aggregates, preamyloid oligomers, or amyloid fibrils. By contrast, in bacteria, protozoa, chromista, fungi, and plants, Hsp104 orthologs are highly conserved and confer huge selective advantages in stress tolerance. Moreover, in fungi, the amyloid remodeling activity of Hsp104 has enabled deployment of prions for various beneficial modalities. Thus, a longstanding conundrum has remained unanswered: how do metazoan cells renature aggregated proteins or resolve amyloid fibrils without Hsp104? Here, we highlight recent advances that unveil the metazoan protein-disaggregase machinery, comprising Hsp110, Hsp70, and Hsp40, which synergize to dissolve disordered aggregates, but are unable to rapidly solubilize stable amyloid fibrils. However, Hsp110, Hsp70, and Hsp40 exploit the slow monomer exchange dynamics of amyloid, and can slowly depolymerize amyloid fibrils from their ends in a manner that is stimulated by small heat shock proteins. Upregulation of this system could have key therapeutic applications in various protein-misfolding disorders. Intriguingly, yeast Hsp104 can interface with metazoan Hsp110, Hsp70, and Hsp40 to rapidly eliminate disease associated amyloid. Thus, metazoan proteostasis is receptive to augmentation with exogenous disaggregases, which opens a number of therapeutic opportunities.

Keywords: Hsp104; Hsp110; Hsp70; metazoa; protein disaggregation.

Figure 1. Hsp110, Hsp70, Hsp40 and sHsps are a disaggregation system in metazoan cells. Heat shock proteins Hsp110, Hsp70, and Hsp40 are capable of dissolving disordered aggregates. For labile aggregates, Hsp110 may only need to operate as a nucleotide exchange factor (NEF) for Hsp70, whereas for more stable aggregates it may need to serve as a NEF for Hsp70, engage substrate, and bind and hydrolyze ATP. Hsp110, Hsp70, and Hsp40 can also slowly depolymerize ordered amyloid substrates from their ends. Rapid amyloid dissolution can be achieved by supplementing Hsp110, Hsp70 and Hsp40 with exogenous Hsp104. Here, fibrils can be fragmented and monomers extracted from anywhere in the fibril (not just the ends), which leads to more rapid dissolution. sHsps can stimulate all of these protein disaggregation reactions, but are not absolutely required.