ArticleThe Journal of biological chemistry2015
Enhanced molecular mobility of ordinarily structured regions drives polyglutamine disease.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 32 citations in OpenAlex.
- Allosteric Modulation of Pathological Ataxin-3 Aggregation: A Path to Spinocerebellar Ataxia Type-3 Therapies.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Polyglutamine expansion induced dynamic misfolding of androgen receptor.Protein science : a publication of the Protein Society · 2025Article
- Evolutionary model of repeat insertions in Ataxin-3 traces the origin of the polyglutamine stretch to an ancestral ubiquitin binding module.Protein science : a publication of the Protein Society · 2024Article
- Label-free autofluorescence lifetime reveals the structural dynamics of ataxin-3 inside droplets formed via liquid-liquid phase separation.Scientific reports · 2023Article
- Article
- Mutant Ataxin-3-Containing Aggregates (MATAGGs) in Spinocerebellar Ataxia Type 3: Dynamics of the Disorder.Molecular neurobiology · 2021Review
- Using protein engineering to understand and modulate aggregation.Current opinion in structural biology · 2020Review
- Targeting Amyloid Aggregation: An Overview of Strategies and Mechanisms.International journal of molecular sciences · 2018Review
- Protein Environment: A Crucial Triggering Factor in Josephin Domain Aggregation: The Role of 2,2,2-Trifluoroethanol.International journal of molecular sciences · 2018Article
- Identification of a novel site of interaction between ataxin-3 and the amyloid aggregation inhibitor polyglutamine binding peptide 1.European journal of mass spectrometry (Chichester, England) · 2018Article
- Thermodynamic and kinetic stability of the Josephin Domain closed arrangement: evidences from replica exchange molecular dynamics.Biology direct · 2017Article
- Article
- Chaperones in Polyglutamine Aggregation: Beyond the Q-Stretch.Frontiers in neuroscience · 2017Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Polyglutamine expansion is a hallmark of nine neurodegenerative diseases, with protein aggregation intrinsically linked to disease progression. Although polyglutamine expansion accelerates protein aggregation, the misfolding process is frequently instigated by flanking domains. For example, polyglutamine expansion in ataxin-3 allosterically triggers the aggregation of the catalytic Josephin domain. The molecular mechanism that underpins this allosteric aggregation trigger remains to be determined. Here, we establish that polyglutamine expansion increases the molecular mobility of two juxtaposed helices critical to ataxin-3 deubiquitinase activity. Within one of these helices, we identified a highly amyloidogenic sequence motif that instigates aggregation and forms the core of the growing fibril. Critically, by mutating residues within this key region, we decrease local structural fluctuations to slow ataxin-3 aggregation. This provides significant insight, down to the molecular level, into how polyglutamine expansion drives aggregation and explains the positive correlation between polyglutamine tract length, protein aggregation, and disease severity.
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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.