Disruption of protein homeostasis is one of the most commonly observed phenomena associated with human diseases. Members of the 70-kDa sub-group of heat shock proteins (Hsp70s) are among the molecular chaperones essential for maintaining protein homeostasis. Hsp70s fulfill this role through ATP-dependent cycles of polypeptide substrate binding and release to facilitate their folding, transport, and degradation. The 110-kDa sub-group (Hsp110s) has been shown to possess a unique function as nucleotide exchange factors (NEFs) necessary for Hsp70 function by promoting ADP release. Previous structural models from fungi illustrate the general mechanism of this NEF activity, yet no models for the human variety exist. Furthermore, the sequence conservation among Hsp110s is low despite the high degree of homology shared between Hsp70s. This suggests a functional difference between the fungal and human Hsp70-Hsp110 chaperone machinery, highlighting a critical gap in knowledge whose traversal could potentially aid the discovery of novel treatments. In this study, we conducted structural analyses on the native human and fungal Hsp70-Hsp110 complexes using single-particle cryo-EM to address this important issue. We discovered that the human complex displays a unique nucleotide requirement contrasting that of the fungal system, providing key insight into the first steps of its distinct mechanism in humans. In addition, our analysis revealed considerable conformational differences between the two complexes that are now the subject of further study. Considering the importance of this machinery, our findings provide a strong foundation for targeting the Hsp70-Hsp110 complex in treating diseases linked to its function including cancers, neurodegeneration, and fungal infections.
Perrott et al. (Sun,) studied this question.