ArticleThe Journal of biological chemistry2012
Structural features and domain organization of huntingtin fibrils.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed.
- Surface-Engineered Precision Nano-Systems for Targeted Treatment of Huntington's Disease: A Review of Recent Advancements.International journal of nanomedicine · 2026Review
- Kinetic Mechanism of Substoichiometric Inhibition of Huntingtin Exon-1 Protein Aggregation by Selenium Nanoparticles.Small science · 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
- Integrative determination of atomic structure of mutant huntingtin exon 1 fibrils implicated in Huntington disease.Nature communications · 2024Article
- Evaluating AlphaFold for Clinical Pharmacology and Pharmacogenetics: A Case-Study of Huntingtin Variants Linked to Huntington's Disease.The AAPS journal · 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
- TDP43 and huntingtin Exon-1 undergo a conformationally specific interaction that strongly alters the fibril formation of both proteins.The Journal of biological chemistry · 2024Article
- Solid-state nuclear magnetic resonance in the structural study of polyglutamine aggregation.Biochemical Society transactions · 2024Review
- Fluorescent protein tagging promotes phase separation and alters the aggregation pathway of huntingtin exon-1.The Journal of biological chemistry · 2024Article
- 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
- Selective observation of semi-rigid non-core residues in dynamically complex mutant huntingtin protein fibrils.Journal of structural biology: X · 2022Article
- Amplification of neurotoxic HTTex1 assemblies in human neurons.Neurobiology of disease · 2021Article
- Huntingtin fibrils with different toxicity, structure, and seeding potential can be interconverted.Nature communications · 2021Article
- Cryo-electron tomography provides topological insights into mutant huntingtin exon 1 and polyQ aggregates.Communications biology · 2021Article
- Effect of spin labelling on the aggregation kinetics of yeast prion protein Ure2.Royal Society open science · 2021Article
- An Expanded Polyproline Domain Maintains Mutant Huntingtin SolubleFrontiers in molecular neuroscience · 2021Article
- Structural Model of the Proline-Rich Domain of Huntingtin Exon-1 Fibrils.Biophysical journal · 2020Article
- Implications of the Orb2 Amyloid Structure in Huntington's Disease.International journal of molecular sciences · 2020Review
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Authors and funding
5 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Misfolding and aggregation of huntingtin is one of the hallmarks of Huntington disease, but the overall structure of these aggregates and the mechanisms by which huntingtin misfolds remain poorly understood. Here we used site-directed spin labeling and electron paramagnetic resonance (EPR) spectroscopy to study the structural features of huntingtin exon 1 (HDx1) containing 46 glutamine residues in its polyglutamine (polyQ) region. Despite some residual structuring in the N terminus, we find that soluble HDx1 is highly dynamic. Upon aggregation, the polyQ domain becomes strongly immobilized indicating significant tertiary or quaternary packing interactions. Analysis of spin-spin interactions does not show the close contact between same residues that is characteristic of the parallel, in-register structure commonly found in amyloids. Nevertheless, the same residues are still within 20 Å of each other, suggesting that polyQ domains from different molecules come into proximity in the fibrils. The N terminus has previously been found to take up a helical structure in fibrils. We find that this domain not only becomes structured, but that it also engages in tertiary or quaternary packing interactions. The existence of spin-spin interactions in this region suggests that such contacts could be made between N-terminal domains from different molecules. In contrast, the C-terminal domain is dynamic, contains polyproline II structure, and lacks pronounced packing interactions. This region must be facing away from the core of the fibrils. Collectively, these data provide new constraints for building structural models of HDx1 fibrils.
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