ArticleStructure (London, England : 1993)2019
Structure of Membrane-Bound Huntingtin Exon 1 Reveals Membrane Interaction and Aggregation Mechanisms.
Article in Structure (London, England : 1993), 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed.
- Stimulating proteasomal degradation in human proteinopathies.The FEBS journal · 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
- Mitochondria serve as a holdout compartment for aggregation-prone proteins hindering efficient degradation.Nature communications · 2026Article
- In vitro, cellular and in vivo studies of amyloid oligomers structure and toxicity: Challenges and advances.Protein science : a publication of the Protein Society · 2026Review
- Post-Translational Modifications of Huntingtin: Mechanistic Insights and Therapeutic Opportunities in Huntington's Disease.International journal of molecular sciences · 2025Review
- Opposing roles for GSK3β and ERK1-dependent phosphorylation of huntingtin during neuronal dysfunction and cell death in Huntington's disease.Cell death & disease · 2025Article
- Differential Effects of Post-translational Modifications on the Membrane Interaction of Huntingtin Protein.ACS chemical neuroscience · 2024Article
- The N17 domain of huntingtin as a multifaceted player in Huntington's disease.Frontiers in molecular biosciences · 2024Review
- 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
- Elucidating the Influence of Lipid Composition on Bilayer Perturbations Induced by the N-terminal Region of the Huntingtin Protein.Biophysica · 2023Article
- Interaction between huntingtin exon 1 and HEAT repeat structure probed by chimeric model proteins.Protein science : a publication of the Protein Society · 2023Article
- Cholesterol impacts the formation of huntingtin/lipid complexes and subsequent aggregation.Protein science : a publication of the Protein Society · 2023Article
- The Dynamic Interactions of a Multitargeting Domain in Ameloblastin Protein with Amelogenin and Membrane.International journal of molecular sciences · 2023Article
- Transmission-selective muscle pathology induced by the active propagation of mutant huntingtin across the human neuromuscular synapse.Frontiers in molecular neuroscience · 2023Article
- Oxidation Promotes Distinct Huntingtin Aggregates in the Presence and Absence of Membranes.Biochemistry · 2022Article
- Huntingtin exon 1 deletion does not alter the subcellular distribution of huntingtin and gene transcription in mice.Frontiers in cellular neuroscience · 2022Article
- Amplification of neurotoxic HTTex1 assemblies in human neurons.Neurobiology of disease · 2021Article
- Mitochondrial membranes modify mutant huntingtin aggregation.Biochimica et biophysica acta. Biomembranes · 2021Article
- Macromolecular crowding in solution alters huntingtin interaction and aggregation at interfaces.Colloids and surfaces. B, Biointerfaces · 2021Article
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Authors and funding
5 authors.
Funding
Abstract
Huntington's disease is caused by a polyQ expansion in the first exon of huntingtin (Httex1). Membrane interaction of huntingtin is of physiological and pathological relevance. Using electron paramagnetic resonance and Overhauser dynamic nuclear polarization, we find that the N-terminal residues 3-13 of wild-type Httex1(Q25) form a membrane-bound, amphipathic α helix. This helix is positioned in the interfacial region, where it is sensitive to membrane curvature and electrostatic interactions with head-group charges. Residues 14-22, which contain the first five residues of the polyQ region, are in a transition region that remains in the interfacial region without taking up a stable, α-helical structure. The remaining C-terminal portion is solvent exposed. The phosphomimetic S13D/S16D mutations, which are known to protect from toxicity, inhibit membrane binding and attenuate membrane-mediated aggregation of mutant Httex1(Q46) due to electrostatic repulsion. Targeting the N-terminal membrane anchor using post-translational modifications or specific binders could be a potential means to reduce aggregation and toxicity in vivo.
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