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Pré-Publication, Document De Travail Année : 2022

The structure of pathogenic huntingtin exon-1 defines the bases of its aggregation propensity

Carlos A Elena-Real
Amin Sagar
Annika Urbanek
  • Fonction : Auteur
Matija Popovic
Anna Morató
Alejandro Estaña
  • Fonction : Auteur
Aurélie Fournet
Xamuel L Lund
Zhen-Dan Shi
  • Fonction : Auteur
Luca Costa
Aurélien Thureau
Frédéric Allemand
Rolf E Swenson
Pierre-Emmanuel Milhiet
Alessandro Barducci
  • Fonction : Auteur
Juan Cortés
  • Fonction : Auteur
Davy Sinnaeve
Pau Bernadó
  • Fonction : Auteur
  • PersonId : 992544

Résumé

Abstract Huntington’s Disease is a neurodegenerative disorder caused by a CAG expansion of the first exon of the HTT gene, resulting in an extended poly-glutamine (poly-Q) tract in the N-terminus of the protein huntingtin (httex1). The structural changes occurring to the poly-Q when increasing its length remain poorly understood mainly due to its intrinsic flexibility and the strong compositional bias of the protein. The systematic application of site-specific isotopic labeling has enabled residue-specific NMR investigations of the poly-Q tract of pathogenic httex1 variants with 46 and 66 consecutive glutamines. The integrative analysis of the data reveals that the poly-Q tract adopts long α-helical conformations stabilized by glutamine side-chain to backbone hydrogen bonds. 19 F-NMR of site-specifically incorporated fluoro-glutamines and molecular dynamics simulations demonstrate that the mechanism propagating α-helical conformations towards the poly-Q from the upstream N17 domain is independent of the poly-Q track length. Aggregation and atomic force microscopy experiments show that the presence of long and persistent α-helices in the poly-Q tract is a stronger signature in defining the aggregation kinetics and the structure of the resulting fibrils than the number of glutamines. The ensemble of our observations provides a structural perspective of the pathogenicity of expanded httex1 and paves the way to a deeper understanding of poly-Q related diseases.
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Dates et versions

hal-03846359 , version 1 (10-11-2022)

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Carlos A Elena-Real, Amin Sagar, Annika Urbanek, Matija Popovic, Anna Morató, et al.. The structure of pathogenic huntingtin exon-1 defines the bases of its aggregation propensity. 2022. ⟨hal-03846359⟩
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