Enhanced molecular mobility of ordinarily structured regions drives polyglutamine disease

Christopher Joseph Lupton, David L Steer, Patrick L Wintrode, Stephen P Bottomley, Victoria A Hughes, Andrew M Ellisdon

Research output: Contribution to journalArticleResearchpeer-review

19 Citations (Scopus)


Polyglutamine expansion is a hallmark of nine neurodegenerative diseases, with protein aggregation intrinsically linked to disease progression. While polyglutamine expansion accelerates protein aggregation, the misfolding process is actually 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.
Original languageEnglish
Pages (from-to)24190 - 24200
Number of pages11
JournalJournal of Biological Chemistry
Issue number40
Publication statusPublished - 2015

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