ArticleBiochemistry2014
Polyglutamine amyloid core boundaries and flanking domain dynamics in huntingtin fragment fibrils determined by solid-state nuclear magnetic resonance.
Article in Biochemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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Who cites it
56 citing papers in PubMed, 87 citations in OpenAlex.
- Probing How Anti-huntingtin Antibodies Bind the Fibrillar Fuzzy Coat Using Solid-State NMR.Chemistry (Weinheim an der Bergstrasse, Germany) · 2025Article
- Direct Observation of Secondary Nucleation in Huntingtin Amyloid Formation by High-Speed Atomic Force Microscopy.Journal of the American Chemical Society · 2025Article
- Inhibitor-based modulation of huntingtin aggregation mechanisms mitigates fibril-induced cellular stress.Nature communications · 2025Article
- Conformational Dynamics of BacteriochlorophyllThe journal of physical chemistry. B · 2025Article
- Integrative determination of atomic structure of mutant huntingtin exon 1 fibrils implicated in Huntington disease.Nature communications · 2024Article
- Integrative determination of the atomic structure of mutant huntingtin exon 1 fibrils implicated in Huntington's disease.bioRxiv : the preprint server for biology · 2024Article
- Solid-state nuclear magnetic resonance in the structural study of polyglutamine aggregation.Biochemical Society transactions · 2024Review
- Kinetic evidence for multiple aggregation pathways in antibody light chain variable domains.Protein science : a publication of the Protein Society · 2024Article
- Article
- Elucidating the Influence of Lipid Composition on Bilayer Perturbations Induced by the N-terminal Region of the Huntingtin Protein.Biophysica · 2023Article
- 3D-Printable centrifugal devices for biomolecular solid state NMR rotors.Journal of magnetic resonance (San Diego, Calif. : 1997) · 2023Article
- Molecular Tweezers: Supramolecular Hosts with Broad-Spectrum Biological Applications.Pharmacological reviews · 2023Review
- Comparative molecular dynamics simulations of pathogenic and non-pathogenic huntingtin protein monomers and dimers.Frontiers in molecular biosciences · 2023Article
- Identification of a HTT-specific binding motif in DNAJB1 essential for suppression and disaggregation of HTT.Nature communications · 2022Article
- Oxidation Promotes Distinct Huntingtin Aggregates in the Presence and Absence of Membranes.Biochemistry · 2022Article
- Quantitative NMR analysis of the kinetics of prenucleation oligomerization and aggregation of pathogenic huntingtin exon-1 protein.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- NMR spectroscopy, excited states and relevance to problems in cell biology - transient pre-nucleation tetramerization of huntingtin and insights into Huntington's disease.Journal of cell science · 2022Article
- Selective observation of semi-rigid non-core residues in dynamically complex mutant huntingtin protein fibrils.Journal of structural biology: X · 2022Article
- Cryo-electron tomography provides topological insights into mutant huntingtin exon 1 and polyQ aggregates.Communications biology · 2021Article
- Membrane Interactions Accelerate the Self-Aggregation of Huntingtin Exon 1 Fragments in a Polyglutamine Length-Dependent Manner.International journal of molecular sciences · 2021Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
In Huntington's disease, expansion of a polyglutamine (polyQ) domain in the huntingtin (htt) protein leads to misfolding and aggregation. There is much interest in the molecular features that distinguish monomeric, oligomeric, and fibrillar species that populate the aggregation pathway and likely differ in cytotoxicity. The mechanism and rate of aggregation are greatly affected by the domains flanking the polyQ segment within exon 1 of htt. A "protective" C-terminal proline-rich flanking domain inhibits aggregation by inducing polyproline II structure (PPII) within an extended portion of polyQ. The N-terminal flanking segment (htt(NT)) adopts an α-helical structure as it drives aggregation, helps stabilize oligomers and fibrils, and is seemingly integral to their supramolecular assembly. Via solid-state nuclear magnetic resonance (ssNMR), we probe how, in the mature fibrils, the htt flanking domains impact the polyQ domain and in particular the localization of the β-structured amyloid core. Using residue-specific and uniformly labeled samples, we find that the amyloid core occupies most of the polyQ domain but ends just prior to the prolines. We probe the structural and dynamical features of the remarkably abrupt β-sheet to PPII transition and discuss the potential connections to certain htt-binding proteins. We also examine the htt(NT) α-helix outside the polyQ amyloid core. Despite its presumed structural and demonstrated stabilizing roles in the fibrils, quantitative ssNMR measurements of residue-specific dynamics show that it undergoes distinct solvent-coupled motion. This dynamical feature seems reminiscent of molten-globule-like α-helix-rich features attributed to the nonfibrillar oligomeric species of various amyloidogenic proteins.
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