ArticleProceedings of the National Academy of Sciences of the United States of America2001
An expanded glutamine repeat destabilizes native ataxin-3 structure and mediates formation of parallel beta -fibrils.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 153 citations in OpenAlex.
- Preventing Protein Self-Association Through Strategic Covalent Modification.Journal of peptide science : an official publication of the European Peptide Society · 2025Article
- The deubiquitinase function of ataxin-3 and its role in the pathogenesis of Machado-Joseph disease and other diseases.The Biochemical journal · 2024Review
- Abnormal phase separation of biomacromolecules in human diseases.Acta biochimica et biophysica Sinica · 2023Review
- Flow cytometry allows rapid detection of protein aggregates in cellular and zebrafish models of spinocerebellar ataxia 3.Disease models & mechanisms · 2021Article
- Article
- Mutant Ataxin-3-Containing Aggregates (MATAGGs) in Spinocerebellar Ataxia Type 3: Dynamics of the Disorder.Molecular neurobiology · 2021Review
- Stress granules, RNA-binding proteins and polyglutamine diseases: too much aggregation?Cell death & disease · 2021Review
- Hexosamine Pathway Activation Improves Protein Homeostasis through the Integrated Stress Response.iScience · 2020Article
- The Mechanisms of Nuclear Proteotoxicity in Polyglutamine Spinocerebellar Ataxias.Frontiers in neuroscience · 2020Review
- From Pathogenesis to Novel Therapeutics for Spinocerebellar Ataxia Type 3: Evading Potholes on the Way to Translation.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2019Review
- Repeat-Associated Non-ATG Translation: Molecular Mechanisms and Contribution to Neurological Disease.Annual review of neuroscience · 2019Review
- Structural and dynamic studies reveal that the Ala-rich region of ataxin-7 initiates α-helix formation of the polyQ tract but suppresses its aggregation.Scientific reports · 2019Article
- Expanded and Wild-type Ataxin-3 Modify the Redox Status of SH-SY5Y Cells Overexpressing α-Synuclein.Neurochemical research · 2017Article
- The Machado-Joseph Disease Deubiquitinase Ataxin-3 Regulates the Stability and Apoptotic Function of p53.PLoS biology · 2016Article
- Polyglutamine Aggregation in Huntington Disease: Does Structure Determine Toxicity?Molecular neurobiology · 2015Review
- The de novo synthesis of ubiquitin: identification of deubiquitinases acting on ubiquitin precursors.Scientific reports · 2015Article
- Examination of Ataxin-3 (atx-3) Aggregation by Structural Mass Spectrometry Techniques: A Rationale for Expedited Aggregation upon Polyglutamine (polyQ) Expansion.Molecular & cellular proteomics : MCP · 2015Article
- Article
- Aggregation of polyglutamine-expanded ataxin-3 sequesters its specific interacting partners into inclusions: implication in a loss-of-function pathology.Scientific reports · 2014Article
- p62/sequestosome 1 regulates aggresome formation of pathogenic ataxin-3 with expanded polyglutamine.International journal of molecular sciences · 2014Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 2 countries.
Funding
Abstract
The protein ataxin-3 contains a polyglutamine region; increasing the number of glutamines beyond 55 in this region gives rise to the neurodegenerative disease spinocerebellar ataxia type 3. This disease and other polyglutamine expansion diseases are characterized by large intranuclear protein aggregates (nuclear inclusions). By using full-length human ataxin-3, we have investigated the changes in secondary structure, aggregation behavior, and fibril formation associated with an increase from the normal length of 27 glutamines (Q27 ataxin-3) to a pathogenic length of 78 glutamines (Q78 ataxin-3). Q78 ataxin-3 aggregates strongly and could be purified only when expressed with a solubility-enhancing fusion-protein partner. A marked decrease in alpha-helical secondary structure accompanies expansion of the polyglutamine tract, suggesting destabilization of the native protein. Proteolytic removal of the fusion partner in the Q78 protein, but not in the Q27 protein, leads to the formation of SDS-resistant aggregates and Congo-red reactive fibrils. Infrared spectroscopy of fibrils reveals a high beta-sheet content and suggests a parallel, rather than an antiparallel, sheet conformation. We present a model for a polar zipper composed of parallel polyglutamine beta-sheets. Our data show that intact ataxin-3 is fully competent to form aggregates, and posttranslational cleavage or other processing is not necessary to generate a misfolding event. The data also suggest that the protein aggregation phenotype associated with glutamine expansion may derive from two effects: destabilization of the native protein structure and an inherent propensity for beta-fibril formation on the part of glutamine homopolymers.
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