Defining functional variation of diverse Hsp104 homologues

Hsp104 is a hexametric AAA+ protein disaggregase from yeast that can rapidly disassemble disordered aggregates, preamyloid oligomers, amyloids, and prions. These protein‐remodeling activities enable resistance to and reversal of stress‐triggered protein misfolding, and have even allowed yeast to harness prions for adaptive purposes. Hsp104 orthologues are found in all nonmetazoan eukaryotes and eubacteria, but the vast majority of these remain unexplored. Thus, Hsp104 sequence space, and the extent of protein‐remodeling activities enabled by it, is unknown. Here, I present our efforts to functionally define diverse Hsp104 homologues from fungal, plant, algal, and protozoan lineages. While these homologues functionally complement various protein‐remodeling activities performed by Hsp104 from S. cerevisiae ( Sc Hsp104), we find, surprisingly, that they are able to antagonize unique and diverse proteotoxic misfolding events under conditions where Sc Hsp104 is inactive. I also present our work to understand the molecular mechanisms underpinning these activities. Our results establish that natural Hsp104 orthologues can have therapeutic‐disaggregase activity against substrates involved in human disease. We suggest that sequence variation among Hsp104 orthologues may be a valuable resource in the engineering of therapeutic disaggregases to counter disease.