1. The structure of pathogenic huntingtin exon 1 defines the bases of its aggregation propensity.
- Author
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Elena-Real CA, Sagar A, Urbanek A, Popovic M, Morató A, Estaña A, Fournet A, Doucet C, Lund XL, Shi ZD, Costa L, Thureau A, Allemand F, Swenson RE, Milhiet PE, Crehuet R, Barducci A, Cortés J, Sinnaeve D, Sibille N, and Bernadó P
- Subjects
- Huntingtin Protein genetics, Huntingtin Protein chemistry, Magnetic Resonance Spectroscopy, Protein Conformation, alpha-Helical, Exons
- 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 polyglutamine (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., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
- Published
- 2023
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