title: Enhanced molecular mobility of ordinarily structured regions drives polyglutamine disease.
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.
authors.affiliation: From the Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, and.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lupton
authors.affiliation: From the Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, and.
authors.forename: David L
authors.initials: DL
authors.lastname: Steer
authors.affiliation: the Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201.
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Wintrode
authors.affiliation: From the Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, and.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Bottomley
authors.affiliation: From the Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, and the Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Melbourne, Victoria, Australia, 3800 and victoria.hughes@monash.edu.
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Hughes
authors.affiliation: From the Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, and the Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Melbourne, Victoria, Australia, 3800 and andrew.ellisdon@monash.edu.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Ellisdon
mesh_terms: D000409:Alanine / Q000737:chemistry; D000495:Allosteric Site; D058227:Amyloidogenic Proteins / Q000737:chemistry; D000067699:Ataxin-3 / Q000737:chemistry*; D052160:Benzothiazoles; D020134:Catalytic Domain; D002851:Chromatography, High Pressure Liquid; D018450:Disease Progression; D004926:Escherichia coli / Q000378:metabolism; D014644:Genetic Variation; D006801:Humans; D017827:Machado-Joseph Disease / Q000378:metabolism*; D046529:Microscopy, Electron, Transmission; D016296:Mutagenesis; D010449:Peptide Mapping; D010455:Peptides / Q000737:chemistry*; D011485:Protein Binding; D017510:Protein Folding; D017433:Protein Structure, Secondary; D053719:Tandem Mass Spectrometry; D013844:Thiazoles / Q000737:chemistry
chemical_list: D058227:Amyloidogenic Proteins; D052160:Benzothiazoles; D010455:Peptides; D013844:Thiazoles; C009462:thioflavin T; C097188:polyglutamine; D000067699:Ataxin-3; D000409:Alanine
keywords: Huntington disease; Machado-Joseph disease; amyloid; ataxia; ataxin-3; molecular dynamics; polyglutamine; protein misfolding; spinocerebellar ataxia type-3