Cited by 66Genetic Neurodegenerative DiseasesProtein Structure and DynamicsPrion Diseases and Protein Misfolding

Flanking regions determine the structure of the poly-glutamine in Huntingtin through mechanisms common among glutamine-rich human proteins

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Urbanek, Annika, Popovic, Matija, Morató, Anna, Estaña, Alejandro, Elena-Real, Carlos A., Mier, Pablo, Fournet, Aurélie, Allemand, Frédéric +5 more·2020·Structure

Abstract

The causative agent of Huntington's disease, the poly-Q homo-repeat in the N-terminal region of huntingtin (httex1), is flanked by a 17-residue-long fragment (N17) and a proline-rich region (PRR), which promote and inhibit the aggregation propensity of the protein, respectively, by poorly understood mechanisms. Based on experimental data obtained from site-specifically labeled NMR samples, we derived an ensemble model of httex1 that identified both flanking regions as opposing poly-Q secondary structure promoters. While N17 triggers helicity through a promiscuous hydrogen bond network involving the side chains of the first glutamines in the poly-Q tract, the PRR promotes extended conformations in neighboring glutamines. Furthermore, a bioinformatics analysis of the human proteome showed that these structural traits are present in many human glutamine-rich proteins and that they are more prevalent in proteins with longer poly-Q tracts. Taken together, these observations provide the structural bases to understand previous biophysical and functional data on httex1.

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Crossref · 10.1016/j.str.2020.04.008

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  • High-resolution structural studies of purely monomeric species are challenging because these molecules tend to self-associate readily.

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Authors
Urbanek, A., Popovic, M., Morató, A., Estaña, A., Elena-Real, C. A., Mier, P., Fournet, A., Allemand, F., Delbecq, S., Andrade-Navarro, M. A., Cortés, J., Sibille, N., & Bernadó, P.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Johannes Gutenberg University Mainz (DE)
Corresponding author
Bernadó, Pau
Venue
Structure
Publisher
Elsevier BV
Published
2020-07
Volume
28
Issue
7
Pages
733-746.e5
ISSN
0969-2126 (ISSN-L)
OpenAlex
W3024496639
Cited by
66
References
84
Citations by year
2026: 5 · 2025: 6 · 2024: 10 · 2023: 12 · 2022: 11 · 2021: 17 · 2020: 5
FWCI
5.17
Type
journal article
Language
en
Open access
Locations
  • Structure (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
Funders
European Research Council
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
Keywords
huntingtin, polyglutamine, N-terminal huntingtin fragments, flanking regions, proline-rich region, protein aggregation, secondary structure, hydrogen bond network, glutamine-rich protein, ensemble learning, Huntington's disease, protein structure
MeSH terms
Huntingtin Protein, Humans, Polyglutamic Acid, Repetitive Sequences, Amino Acid, Amino Acid Motifs, Intrinsically Disordered Proteins

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