Enhanced Molecular Mobility of Ordinarily Structured Regions Drives Polyglutamine Disease

• Published in: The Journal of biological chemistry Vol. 290; no. 40; pp. 24190 - 24200
• Main Authors: Lupton, Christopher J., Steer, David L., Wintrode, Patrick L., Bottomley, Stephen P., Hughes, Victoria A., Ellisdon, Andrew M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.10.2015; American Society for Biochemistry and Molecular Biology
• Subjects: Alanine - chemistry; Allosteric Site; amyloid; Amyloidogenic Proteins - chemistry; ataxia; ataxin-3; Ataxin-3 - chemistry; Benzothiazoles; Catalytic Domain; Chromatography, High Pressure Liquid; Disease Progression; Escherichia coli - metabolism; Genetic Variation; Humans; Huntington disease; Machado-Joseph disease; Machado-Joseph Disease - metabolism; Microscopy, Electron, Transmission; molecular dynamics; Mutagenesis; Peptide Mapping; Peptides - chemistry; polyglutamine; Protein Binding; Protein Folding; protein misfolding; Protein Structure and Folding; Protein Structure, Secondary; spinocerebellar ataxia type-3; Tandem Mass Spectrometry; Thiazoles - chemistry; spinocerebellar ataxia type-3; ataxin-3; amyloid; Machado-Joseph disease; ataxia; protein misfolding; Huntington disease; molecular dynamics; polyglutamine
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.659532

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. Background: Polyglutamine tract expansion within disease-associated proteins leads to protein aggregation and disease. Results: Molecular mobility of a single α-helix within ataxin-3 positively scales with polyglutamine tract length and drives misfolding and aggregation. Conclusion: Polyglutamine expansion allosterically enhances the molecular dynamics of folded regions to trigger amyloid-like fibril formation. Significance: This work resolves the mechanistic link between polyglutamine tract length and aggregation.