Author response: Structural basis for the disaggregase activity and regulation of Hsp104

Heuck, Alexander; Schitter-Sollner, Sonja; Suskiewicz, Marcin; Kurzbauer, R; Kley, Juliane; Schleiffer, Alexander; Rombaut, Pascaline; Herzog, Franz; Clausen, Tim

doi:10.7554/elife.21516.034

2016

DOI: 10.7554/elife.21516.034

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Author response: Structural basis for the disaggregase activity and regulation of Hsp104

Alexander Heuck

Sonja Schitter-Sollner

Marcin Suskiewicz

et al.

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Tuning Hsp104 specificity to selectively detoxify α-synuclein

Mack

Kim

Jackrel³

et al. 2020

Preprint

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Hsp104 is an AAA+ protein disaggregase that solubilizes and reactivates proteins trapped in aggregated states. We have engineered potentiated Hsp104 variants to mitigate toxic misfolding of α-synuclein, TDP-43, and FUS implicated in fatal neurodegenerative disorders. Though potent disaggregases, these enhanced Hsp104 variants lack substrate specificity, and can have unfavorable off-target effects. Here, to lessen off-target effects, we engineer substrate-specific Hsp104 variants. By altering Hsp104 pore loops that engage substrate, we disambiguate Hsp104 variants that selectively suppress α-synuclein toxicity but not TDP-43 or FUS toxicity. Remarkably, αsynuclein-specific Hsp104 variants emerge that mitigate α-synuclein toxicity via distinct ATPase-dependent mechanisms, involving α-synuclein disaggregation or detoxification of α-synuclein conformers without disaggregation. Importantly, both types of α-synucleinspecific Hsp104 variant reduce dopaminergic neurodegeneration in a C. elegans model of Parkinson's disease more effectively than non-specific variants. We suggest that increasing the substrate specificity of enhanced disaggregases could be applied broadly to tailor therapeutics for neurodegenerative disease.

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Tuning Hsp104 specificity to selectively detoxify α-synuclein

Mack

Kim

Jackrel³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

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Author response: Structural basis for the disaggregase activity and regulation of Hsp104

Cited by 1 publication

References 0 publications

Tuning Hsp104 specificity to selectively detoxify α-synuclein

Tuning Hsp104 specificity to selectively detoxify α-synuclein

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