Operational Plasticity Enables Hsp104 to Disaggregate Diverse Amyloid and Nonamyloid Clients

It is not understood how Hsp104, a hexameric AAA+ ATPase from yeast, disaggregates diverse structures, including stress-induced aggregates, prions, and α-synuclein conformers connected to Parkinson disease. Here, we establish that Hsp104 hexamers adapt different mechanisms of intersubunit collaboration to disaggregate stress-induced aggregates versus amyloid. To resolve disordered aggregates, Hsp104 subunits collaborate noncooperatively via probabilistic substrate binding and ATP hydrolysis. To disaggregate amyloid, several subunits cooperatively engage substrate and hydrolyze ATP. Importantly, Hsp104 variants with impaired intersubunit communication dissolve disordered aggregates, but not amyloid. Unexpectedly, prokaryotic ClpB subunits collaborate differently than Hsp104 and couple probabilistic substrate binding to cooperative ATP hydrolysis, which enhances disordered aggregate dissolution but sensitizes ClpB to inhibition and diminishes amyloid disaggregation. Finally, we establish that Hsp104 hexamers deploy more subunits to disaggregate Sup35 prion strains with more stable “cross-β” cores. Thus, operational plasticity enables Hsp104 to robustly dissolve amyloid and nonamyloid clients, which impose distinct mechanical demands. [Display omitted] ► Hsp104 switches mechanism to disaggregate disordered aggregates versus amyloid ► ClpB operates with reduced plasticity and has limited amyloid-disaggregase activity ► Hsp104 remodels diverse toxic oligomers and amyloids linked to neurodegeneration ► Hsp104 plasticity enables yeast to harness prions for advantageous purposes The protein disaggregase Hsp104 from yeast employs different mechanisms to resolve disordered aggregates versus amyloid. Conversely, its bacterial homolog ClpB displays reduced operational plasticity and limited amyloid-remodeling activity.