A compact β model of huntingtin toxicity

Qi Charles Zhang, Tzu Lan Yeh, Alfonso Leyva, Leslie G. Frank, Jason Miller, Yujin E. Kim, Ralf Langen, Steven Finkbeiner, Mario L. Amzel, Christopher A. Ross, Michelle A. Poirier

Research output: Contribution to journalArticlepeer-review

Abstract

Huntington disease results from an expanded polyglutamine region in the N terminus of the huntingtin protein. HD pathology is characterized by neuronal degeneration and protein inclusions containing N-terminal fragments of mutant huntingtin. Structural information is minimal, though it is believed that mutant huntingtin polyglutamine adopts β structure upon conversion to a toxic form. To this end, we designed mammalian cell expression constructs encoding compact β variants of Htt exon 1 N-terminal fragment and tested their ability to aggregate and induce toxicity in cultured neuronal cells. In parallel, we performed molecular dynamics simulations, which indicate that constructs with expanded polyglutamine β-strands are stabilized by main-chain hydrogen bonding. Finally, we found a correlation between the reactivity to 3B5H10, an expanded polyglutamine antibody that recognizes a compact β rich hairpin structure, and the ability to induce cell toxicity. These data are consistent with an important role for a compact β structure in mutant huntingtin-induced cell toxicity.

Original languageEnglish (US)
Pages (from-to)8188-8196
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number10
DOIs
StatePublished - Mar 11 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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