Journal article
An expanded glutamine repeat destabilizes native ataxin-3 structure and mediates formation of parallel β-fibrils
Proceedings of the National Academy of Sciences - PNAS, v 98(21), pp 11955-11960
09 Oct 2001
PMID: 11572942
Featured in Collection : UN Sustainable Development Goals @ Drexel
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 α-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 β-sheet content and suggests a parallel, rather than an antiparallel, sheet conformation. We present a model for a polar zipper composed of parallel polyglutamine β-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 β-fibril formation on the part of glutamine homopolymers.
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Details
- Title
- An expanded glutamine repeat destabilizes native ataxin-3 structure and mediates formation of parallel β-fibrils
- Creators
- Anthony E Bevivino - Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104-6084Patrick J Loll - Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104-6084
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, v 98(21), pp 11955-11960
- Publisher
- The National Academy of Sciences
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000171558900026
- Scopus ID
- 2-s2.0-0035833997
- Other Identifier
- 991014878107204721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology