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The aggregation-enhancing huntingtin N-terminus is helical in amyloid fibrils

Sivanandam, VN and Jayaraman, M and Hoop, CL and Kodali, R and Wetzel, R and Van Der Wel, PCA (2011) The aggregation-enhancing huntingtin N-terminus is helical in amyloid fibrils. Journal of the American Chemical Society, 133 (12). 4558 - 4566. ISSN 0002-7863

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Abstract

The 17-residue N-terminus (httNT) directly flanking the polyQ sequence in huntingtin (htt) N-terminal fragments plays a crucial role in initiating and accelerating the aggregation process that is associated with Huntington's disease pathogenesis. Here we report on magic-angle-spinning solid-state NMR studies of the amyloid-like aggregates of an htt N-terminal fragment. We find that the polyQ portion of this peptide exists in a rigid, dehydrated amyloid core that is structurally similar to simpler polyQ fibrils and may contain antiparallel β-sheets. In contrast, the httNT sequence in the aggregates is composed in part of a well-defined helix, which likely also exists in early oligomeric aggregates. Further NMR experiments demonstrate that the N-terminal helical segment displays increased dynamics and water exposure. Given its specific contribution to the initiation, rate, and mechanism of fibril formation, the helical nature of httNT and its apparent lack of effect on the polyQ fibril core structure seem surprising. The results provide new details about these disease-associated aggregates and also provide a clear example of an amino acid sequence that greatly enhances the rate of amyloid formation while itself not taking part in the amyloid structure. There is an interesting mechanistic analogy to recent reports pointing out the early-stage contributions of transient intermolecular helix-helix interactions in the aggregation behavior of various other amyloid fibrils. © 2011 American Chemical Society.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Sivanandam, VN
Jayaraman, M
Hoop, CL
Kodali, R
Wetzel, Rrwetzel@pitt.eduRWETZEL
Van Der Wel, PCApvdwel@pitt.eduPVDWEL0000-0002-5390-3321
Date: 30 March 2011
Date Type: Publication
Journal or Publication Title: Journal of the American Chemical Society
Volume: 133
Number: 12
Page Range: 4558 - 4566
DOI or Unique Handle: 10.1021/ja110715f
Schools and Programs: School of Medicine > Structural Biology
Refereed: Yes
ISSN: 0002-7863
Date Deposited: 25 Apr 2017 18:24
Last Modified: 19 Jun 2021 10:55
URI: http://d-scholarship.pitt.edu/id/eprint/31014

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