Tadpole-like Conformations of Huntingtin Exon 1 Are Characterized by Conformational Heterogeneity that Persists regardless of Polyglutamine Length

Estella A. Newcombe, Kiersten M. Ruff, Ashish Sethi, Angelique R Ormsby, Yasmin M. Ramdzan, Archa H. Fox, Anthony W. Purcell, Paul Raymond Gooley, Rohit V. Pappu, Danny M. Hatters

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22 Citations (Scopus)

Abstract

Soluble huntingtin exon 1 (Httex1) with expanded polyglutamine (polyQ) engenders neurotoxicity in Huntington's disease. To uncover the physical basis of this toxicity, we performed structural studies of soluble Httex1 for wild-type and mutant polyQ lengths. Nuclear magnetic resonance experiments show evidence for conformational rigidity across the polyQ region. In contrast, hydrogen–deuterium exchange shows absence of backbone amide protection, suggesting negligible persistence of hydrogen bonds. The seemingly conflicting results are explained by all-atom simulations, which show that Httex1 adopts tadpole-like structures with a globular head encompassing the N-terminal amphipathic and polyQ regions and the tail encompassing the C-terminal proline-rich region. The surface area of the globular domain increases monotonically with polyQ length. This stimulates sharp increases in gain-of-function interactions in cells for expanded polyQ, and one of these interactions is with the stress-granule protein Fus. Our results highlight plausible connections between Httex1 structure and routes to neurotoxicity.

Original languageEnglish
Pages (from-to)1442-1458
Number of pages17
JournalJournal of Molecular Biology
Volume430
Issue number10
DOIs
Publication statusPublished - 11 May 2018

Keywords

  • Huntington's disease
  • hydrogen–deuterium exchange
  • molecular simulations
  • NMR spectroscopy

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