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 Fox, Anthony W Purcell, Paul R. Gooley, Rohit V Pappu, Danny M Hatters

Research output: Contribution to journalArticle

20 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

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