The structure of pathogenic huntingtin exon 1 defines the bases of its aggregation propensity - LAAS - Laboratoire d'Analyse et d'Architecture des Systèmes Accéder directement au contenu
Article Dans Une Revue Nature Structural and Molecular Biology Année : 2023

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

Luca Costa
Aurélien Thureau
Juan Cortés
Pau Bernadó

Résumé

Huntington’s Disease is a neurodegenerative disorder caused by a CAG expansion in the first exon of the HTT gene, resulting in an extended poly-glutamine (poly-Q) tract in huntingtin (httex1). The structural changes occurring to the poly-Q when increasing its length remain poorly understood due to its intrinsic flexibility and the strong compositional bias. 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. Integrative data analysis reveals that the poly-Q tract adopts long α-helical conformations propagated and stabilized by glutamine side chain to backbone hydrogen bonds. We show that α-helical stability is a stronger signature in defining aggregation kinetics and the structure of the resulting fibrils than the number of glutamines. Our observations provide a structural perspective of the pathogenicity of expanded httex1 and pave the way to a deeper understanding of poly-Q-related diseases.
Fichier principal
Vignette du fichier
Elena_Real_et_al_NSMB_2023_ms.pdf (1.64 Mo) Télécharger le fichier
Elena_Real_et_al_NSMB_2023_SI.pdf (13.68 Mo) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)
Licence : Copyright (Tous droits réservés)
Licence : Copyright (Tous droits réservés)

Dates et versions

hal-04052774 , version 1 (30-03-2023)

Identifiants

Citer

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. Nature Structural and Molecular Biology, 2023, 30 (3), pp.309 - 320. ⟨10.1038/s41594-023-00920-0⟩. ⟨hal-04052774⟩
58 Consultations
58 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More