Skd3 (human<i>CLPB</i>) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations

Cupo, Ryan R.; Shorter, James

doi:10.1101/2020.01.17.911016

Cited by 3 publications

(2 citation statements)

References 117 publications

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“…We envision that increasing the substrate specificity of enhanced disaggregases could be applied broadly to tailor therapeutics for neurodegenerative disease. Beyond Hsp104, we anticipate that fine-tuning disaggregases found in humans, such as Hsp110, Hsp70, and Hsp40, nuclear-import receptors, or Skd3 will also be immensely valuable (Cupo and Shorter, 2020;Guo et al, 2019;Guo et al, 2018;Mack and Shorter, 2016;Shorter, 2011Shorter, , 2017. We suggest that highly tuned, specific disaggregases that reverse targeted toxic misfolding events represent an exciting avenue for therapeutic agents in neurodegenerative disease Shorter, 2017).…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

Tuning Hsp104 specificity to selectively detoxify α-synuclein

Mack

Kim

Jackrel³

et al. 2020

Preprint

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“…COA7 Flag however, did enrich a number of IMS proteins, including apoptosis-inducing factor 1 (AIFM1) and CHCHD4, which are required for disulfide bond formation in the intermembrane space (27). In addition, COA7 was able to enrich coproporphyrinogen oxidase (CPOX), an enzyme involved in heme biosynthesis (28), the mitochondrial protease LONP1 (29) and the disaggregase CLPB and the CLPB-interacting protein HAX1 (30) ( Fig. 1 F; Dataset S2 ).…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial COA7 is a heme-binding protein involved in the early stages of complex IV assembly

Formosa

Maghool²,

Sharpe

et al. 2021

Preprint

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Cytochrome c oxidase assembly factor 7 (COA7) is a metazoan-specific assembly factor, critical for the biogenesis of mitochondrial complex IV (cytochrome c oxidase). Although mutations in COA7 have been linked in patients to complex IV assembly defects and neurological conditions such as peripheral neuropathy, ataxia and leukoencephalopathy, the precise role COA7 plays in the biogenesis of complex IV is not known. Here we show that the absence of COA7 leads to arrest of the complex IV assembly pathway at the initial step where the COX1 module is built, which requires incorporation of copper and heme cofactors. In solution, purified COA7 binds heme with micromolar affinity, through axial ligation to the central iron atom by histidine and methionine residues. Surprisingly, the crystal structure of COA7, determined to 2.4 angstroms resolution, reveals a banana-shaped molecule composed of five helix-turn-helix repeats, tethered by disulfide bonds, with a structure entirely distinct from proteins with characterized heme binding activities. We therefore propose a role for COA7 in heme binding/chaperoning in the mitochondrial intermembrane space, this activity being crucial for and providing a missing link in complex IV biogenesis.

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The luminal AAA+ ATPase torsinA mediates distinct mechanisms of nuclear-cytoplasmic communication by adopting different functional assembly states

Hur

Hennen

Saunders

et al. 2021

Preprint

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Chemical and mechanical nuclear-cytoplasmic communication across the nuclear envelope (NE) is largely mediated by the nuclear pore complex (NPC) and the linker of nucleoskeleton and cytoskeleton (LINC) complex, respectively. While NPC and LINC complex assembly are functionally related, the mechanisms responsible for this relationship remain poorly understood. Here, we investigated how the luminal ATPases associated with various cellular activities (AAA+) protein torsinA promotes NPC and LINC complex assembly using fluorescence fluctuation spectroscopy (FFS), quantitative photobleaching analyses, and functional cellular assays. We report that torsinA controls LINC complex-dependent nuclear-cytoskeletal coupling as a soluble hexameric AAA+ protein and interphase NPC biogenesis as a membrane-associated helical polymer. These findings help resolve the conflicting models of torsinA function that were recently proposed based on in vitro structural studies. Our results will enable future studies of the role of defective nuclear-cytoplasmic communication in DYT1 dystonia and other diseases caused by mutations in torsinA.

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Skd3 (humanCLPB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations

Cited by 3 publications

References 117 publications

Tuning Hsp104 specificity to selectively detoxify α-synuclein

Tuning Hsp104 specificity to selectively detoxify α-synuclein

Mitochondrial COA7 is a heme-binding protein involved in the early stages of complex IV assembly

The luminal AAA+ ATPase torsinA mediates distinct mechanisms of nuclear-cytoplasmic communication by adopting different functional assembly states

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