Beta conformation of polyglutamine track revealed by a crystal structure of huntingtin N-terminal region with insertion of three histidine residues

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Abstract

Huntington disease is an autosomal-dominant neurodegenerative disorder caused by a polyglutamine (polyQ) expansion (> 35Q) in the first exon (EX1) of huntingtin protein (Htt). mHtt protein is thought to adopt one or more toxic conformation(s) that are involved in pathogenic interactions in cells. However, the structure of mHtt is not known. Here, we present a near atomic resolution structure of mHtt36Q-EX1. To facilitate crystallization, three histidine residues (3H) were introduced within the Htt36Q stretch resulting in the sequence of Q7HQHQHQ27. The Htt36Q3H region adopts α-helix, loop, β-hairpin conformations. Furthermore, we observed interactions between the backbone of the Htt36Q3H β-strand with the aromatic residues mimicking putative-toxic interactions with other proteins. Our findings support previous predictions that the expanded mHtt-polyQ region adopts a β-sheet structure. Detailed structural information about mHtt improves our understanding of the pathogenic mechanisms in HD and other polyQ expansion disorders and may form the basis for rational design of small molecules that target toxic conformations of disease-causing proteins.

Original languageEnglish (US)
Pages (from-to)221-228
Number of pages8
JournalPrion
Volume7
Issue number3
DOIs
Publication statusPublished - May 2013

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Keywords

  • β-strand
  • β-turn
  • Aggregation
  • Amyloid
  • Ataxia
  • Crystallography
  • Hairpin
  • Huntingtin
  • Polyglutamine
  • Prion

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Infectious Diseases
  • Cellular and Molecular Neuroscience

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