Flanking regions determine the structure of the poly-glutamine in Huntingtin through mechanisms common among glutamine-rich human proteins
Open accessAbstract
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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High-resolution structural studies of purely monomeric species are challenging because these molecules tend to self-associate readily.
“High-resolution structural studies of purely monomeric species are challenging because these molecules tend to selfassociate readily.89,90”
From AlphaFold and Implications for Intrinsically Disordered Proteins (2021) · cites this paper as [90]
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AlphaFold and Implications for Intrinsically Disordered Proteins
Ruff, K. M., & Pappu, R. V. (2021) · Journal of Molecular Biology · doi:10.1016/j.jmb.2021.167208 · Cited by 635 · see citing works
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Self-citation
- 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
- ORCID
- 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
- bronze
- doi.org
- Licence
- 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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