Abstract
Heat shock protein 104 (HSP104) is a conserved AAA+ protein disaggregase, can disassemble the toxic aggregates formed by different amyloid proteins, and is protective in various animal models associated with amyloid-related diseases. Extensive studies have attempted to elucidate how HSP104 disassembles the aggregated form of clients. Here, we found that HSP104 exhibits a potent holdase activity that does not require energy, prevents the soluble form of amyloid clients from aggregating, and differs from HSP104's disaggregase activity. Using cryo-EM, NMR, and additional biophysical approaches, we found that HSP104 utilizes its small subdomain of nucleotide-binding domain 2 (ssNBD2) to capture the soluble amyloid client (K19 of Tau) independent of its ATP hydrolysis activity. Our results indicate that HSP104 utilizes two fundamental distinct mechanisms to chaperone different forms of amyloid client and highlight the important yet previously unappreciated function of ssNBD2 in chaperoning amyloid client and thereby preventing pathological aggregation.
Highlights
Heat shock protein 104 (HSP104) is a conserved AAA؉ protein disaggregase, can disassemble the toxic aggregates formed by different amyloid proteins, and is protective in various animal models associated with amyloid-related diseases
HSP104, acting as a disaggregase of amyloid fibrils, has been intensively investigated [13, 32], we found that HSP104 can efficiently modulate the amyloid aggregation of K19 [33], the three-repeat isoform that forms the fibril core of Tau
ATP, magnesium ions, and co-chaperones (e.g. HSP70 and HSP40), which are essential for HSP104 disaggregase activity [27], are not required in this process, suggesting that the chaperone activity of HSP104 in modulating K19 fibril formation is distinct from its disaggregase activity
Summary
Heat shock protein 104 (HSP104) chaperones soluble Tau via a mechanism distinct from its disaggregase activity. We found that HSP104 exhibits a potent holdase activity that does not require energy, prevents the soluble form of amyloid clients from aggregating, and differs from HSP104’s disaggregase activity. Unlike its HSP100 homologs from other organisms, HSP104 exhibits a potent disaggregase activity on amorphous protein aggregates and on a variety of pathological amyloid fibrils with cross- structures such as Tau, A, ␣-synuclein, and TDP43 [13,14,15,16,17,18]. We found that, in addition to disassembling aggregated proteins, HSP104 can act as a holdase to capture the soluble form of amyloid client K19 of Tau and protect it from. Our results provide the structural basis of the interplay between HSP104 and soluble amyloid client, suggesting that HSP104 utilizes distinct strategies to tackle different forms of amyloid clients
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