The structure of pathogenic huntingtin exon 1 defines the bases of its aggregation propensity - LAAS - Laboratoire d'Analyse et d'Architecture des Systèmes Access content directly
Journal Articles Nature Structural and Molecular Biology Year : 2023

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

Luca Costa
Aurélien Thureau
Juan Cortés
Pau Bernadó

Abstract

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.
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Dates and versions

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

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