ArticleThe Journal of biological chemistry2018
The 17-residue-long N terminus in huntingtin controls stepwise aggregation in solution and on membranes via different mechanisms.
Article in The Journal of biological chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 95 citations in OpenAlex.
- Are Signal Peptides Hidden Regulators of Neurodegenerative Disease?Biomedicines · 2026Review
- Lipid Composition Drives Mutant Huntingtin Dimerization and Membrane Association: Insights from Computational Simulations.Molecules (Basel, Switzerland) · 2026Article
- Lipid composition controls the huntingtin exon 1 membrane-association and differentially modulates its flanking regions' dynamics.Protein science : a publication of the Protein Society · 2026Article
- Rationally Engineered Small Molecules: Pharmacophore Modeling and Molecular Docking Studies Targeting Toxic Polyglutamine (PolyQ) Repeats in Huntington's Disease.Current drug targets · 2026Article
- Kinetic Mechanism of Substoichiometric Inhibition of Huntingtin Exon-1 Protein Aggregation by Selenium Nanoparticles.Small science · 2025Article
- Protofibril Binding Peptides Recognize and Inhibit Huntingtin Amyloid FormationbioRxiv : the preprint server for biology · 2025Article
- Regulation of Mutant Huntingtin Mitochondrial Toxicity by Phosphomimetic Mutations within Its N-Terminal Region.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- Engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtin.Nature communications · 2025Article
- Small HSPs at the crossroad between protein aggregation, autophagy and unconventional secretion: clinical implications and potential therapeutic opportunities in the context of neurodegenerative diseases.Frontiers in cell and developmental biology · 2025Review
- Deuterium trafficking, mitochondrial dysfunction, copper homeostasis, and neurodegenerative disease.Frontiers in molecular biosciences · 2025Review
- 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
- Reviewing the Structure-Function Paradigm in Polyglutamine Disorders: A Synergistic Perspective on Theoretical and Experimental Approaches.International journal of molecular sciences · 2024Review
- Differential Effects of Post-translational Modifications on the Membrane Interaction of Huntingtin Protein.ACS chemical neuroscience · 2024Article
- A method for the analysis of the oligomerization profile of the Huntington's disease-associated, aggregation-prone mutant huntingtin protein by isopycnic ultracentrifugation.Frontiers in molecular biosciences · 2024Article
- The N17 domain of huntingtin as a multifaceted player in Huntington's disease.Frontiers in molecular biosciences · 2024Review
- Article
- Fluorescent protein tagging promotes phase separation and alters the aggregation pathway of huntingtin exon-1.The Journal of biological chemistry · 2024Article
- Charge within Nt17 peptides modulates huntingtin aggregation and initial lipid binding events.Biophysical chemistry · 2023Article
- Elucidating the Influence of Lipid Composition on Bilayer Perturbations Induced by the N-terminal Region of the Huntingtin Protein.Biophysica · 2023Article
- Huntingtin Interacting Proteins and Pathological Implications.International journal of molecular sciences · 2023Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Aggregation of huntingtin protein arising from expanded polyglutamine (polyQ) sequences in the exon-1 region of mutant huntingtin plays a central role in the pathogenesis of Huntington's disease. The huntingtin aggregation pathways are of therapeutic and diagnostic interest, but obtaining critical information from the physiologically relevant htt exon-1 (Httex1) protein has been challenging. Using biophysical techniques and an expression and purification protocol that generates clean, monomeric Httex1, we identified and mapped three distinct aggregation pathways: 1) unseeded in solution; 2) seeded in solution; and 3) membrane-mediated. In solution, aggregation proceeded in a highly stepwise manner, in which the individual domains (N terminus containing 17 amino acids (N17), polyQ, and proline-rich domain (PRD)) become ordered at very different rates. The aggregation was initiated by an early oligomer requiring a pathogenic, expanded Gln length and N17 α-helix formation. In the second phase, β-sheet forms in the polyQ. The slowest step is the final structural maturation of the PRD. This stepwise mechanism could be bypassed by seeding, which potently accelerated aggregation and was a prerequisite for prion-like spreading
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