ArticleACS chemical biology2015
Disparate Mutations Confer Therapeutic Gain of Hsp104 Function.
Article in ACS chemical biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 40 citations in OpenAlex.
- High-throughput screening approach identifies substrate-selective Hsp104 variants that counter amyloid seeding with diminished off-target effects.Molecular cell · 2026Article
- Design principles to tailor Hsp104 therapeutics.Cell reports · 2024Article
- Design principles to tailor Hsp104 therapeutics.bioRxiv : the preprint server for biology · 2024Article
- HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species.Nature communications · 2024Article
- Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD.Molecular neurodegeneration · 2024Review
- Human herpesvirus 8 ORF57 protein is able to reduce TDP-43 pathology: network analysis identifies interacting pathways.Human molecular genetics · 2023Article
- Tuning Hsp104 specificity to selectively detoxify α-synuclein.Molecular cell · 2023Article
- Probing the drivers ofmBio · 2023Article
- Amyloid Fragmentation and Disaggregation in Yeast and Animals.Biomolecules · 2021Review
- Drivers of Hsp104 potentiation revealed by scanning mutagenesis of the middle domain.Protein science : a publication of the Protein Society · 2021Article
- Prion-Like Proteins in Phase Separation and Their Link to Disease.Biomolecules · 2021Review
- Article
- The clinical trial landscape in amyotrophic lateral sclerosis-Past, present, and future.Medicinal research reviews · 2020Review
- Article
- Structural and kinetic basis for the regulation and potentiation of Hsp104 function.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Structural and mechanistic insights into Hsp104 function revealed by synchrotron X-ray footprinting.The Journal of biological chemistry · 2020Article
- Article
- Spiraling in Control: Structures and Mechanisms of the Hsp104 Disaggregase.Cold Spring Harbor perspectives in biology · 2019Review
- Engineered protein disaggregases mitigate toxicity of aberrant prion-like fusion proteins underlying sarcoma.The Journal of biological chemistry · 2019Article
- Structural basis for substrate gripping and translocation by the ClpB AAA+ disaggregase.Nature communications · 2019Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Hsp104, a protein disaggregase from yeast, can be engineered and potentiated to counter TDP-43, FUS, or α-synuclein misfolding and toxicity implicated in neurodegenerative disease. Here, we reveal that extraordinarily disparate mutations potentiate Hsp104. Remarkably, diverse single missense mutations at 20 different positions interspersed throughout the middle domain (MD) and small domain of nucleotide-binding domain 1 (NBD1) confer a therapeutic gain of Hsp104 function. Moreover, potentiation emerges from deletion of MD helix 3 or 4 or via synergistic missense mutations in the MD distal loop and helix 4. We define the most critical aspect of Hsp104 potentiation as enhanced disaggregase activity in the absence of Hsp70 and Hsp40. We suggest that potentiation likely stems from a loss of a fragilely constrained autoinhibited state that enables precise spatiotemporal regulation of disaggregase activity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.