Enhanced Molecular Mobility of Ordinarily Structured Regions Drives Polyglutamine Disease*
| Autor: | Andrew M. Ellisdon, Patrick L. Wintrode, Stephen P. Bottomley, David Steer, Christopher J. Lupton, Victoria A Hughes |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Protein Folding
Amyloid Allosteric regulation Amyloidogenic Proteins Plasma protein binding Protein aggregation Biology Fibril Biochemistry Peptide Mapping Protein Structure Secondary Microscopy Electron Transmission Tandem Mass Spectrometry Catalytic Domain Escherichia coli Humans Benzothiazoles Ataxin-3 Molecular Biology Chromatography High Pressure Liquid Genetics Alanine Genetic Variation Cell Biology Machado-Joseph Disease Polyglutamine tract Thiazoles Mutagenesis Protein Structure and Folding Biophysics Disease Progression Protein folding Sequence motif Peptides Allosteric Site Protein Binding |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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