ArticlePLoS computational biology2010
Polyglutamine induced misfolding of huntingtin exon1 is modulated by the flanking sequences.
Article in PLoS computational biology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 103 citations in OpenAlex.
- Evolutionary perspective of the CAG/CAA interplay coding for pure polyglutamine stretches in proteins.NAR genomics and bioinformatics · 2025Article
- 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
- Big versus small: The impact of aggregate size in disease.Protein science : a publication of the Protein Society · 2023Review
- Comparative molecular dynamics simulations of pathogenic and non-pathogenic huntingtin protein monomers and dimers.Frontiers in molecular biosciences · 2023Article
- Hunting for the cause: Evidence for prion-like mechanisms in Huntington's disease.Frontiers in neuroscience · 2022Review
- Defining the Neuropathological Aggresome acrossThe journal of physical chemistry. B · 2021Review
- An Expanded Polyproline Domain Maintains Mutant Huntingtin SolubleFrontiers in molecular neuroscience · 2021Article
- Nanoscopic Insights of Amphiphilic Peptide against the Oligomer Assembly Process to Treat Huntington's Disease.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2020Article
- Reconstruction of fish allergenicity from the content and structural traits of the component β-parvalbumin isoforms.Scientific reports · 2019Article
- Molecular mechanisms of heterogeneous oligomerization of huntingtin proteins.Scientific reports · 2019Article
- N-terminal Huntingtin (Htt) phosphorylation is a molecular switch regulating Htt aggregation, helical conformation, internalization, and nuclear targeting.The Journal of biological chemistry · 2018Article
- Temperature-induced collapse of a disordered peptide observed by three sampling methods in molecular dynamics simulations.The Journal of chemical physics · 2018Article
- Molecular and structural architecture of polyQ aggregates in yeast.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Studying Huntington's Disease in Yeast: From Mechanisms to Pharmacological Approaches.Frontiers in molecular neuroscience · 2018Review
- Monomeric Huntingtin Exon 1 Has Similar Overall Structural Features for Wild-Type and Pathological Polyglutamine Lengths.Journal of the American Chemical Society · 2017Article
- Emerging β-Sheet Rich Conformations in Supercompact Huntingtin Exon-1 Mutant Structures.Journal of the American Chemical Society · 2017Article
- Assembly of Huntingtin headpiece into α-helical bundles.Biointerphases · 2017Article
- Aggregation landscapes of Huntingtin exon 1 protein fragments and the critical repeat length for the onset of Huntington's disease.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Review
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Authors and funding
3 authors at 1 institution in 1 country.
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Abstract
Polyglutamine (polyQ) expansion in exon1 (XN1) of the huntingtin protein is linked to Huntington's disease. When the number of glutamines exceeds a threshold of approximately 36-40 repeats, XN1 can readily form amyloid aggregates similar to those associated with disease. Many experiments suggest that misfolding of monomeric XN1 plays an important role in the length-dependent aggregation. Elucidating the misfolding of a XN1 monomer can help determine the molecular mechanism of XN1 aggregation and potentially help develop strategies to inhibit XN1 aggregation. The flanking sequences surrounding the polyQ region can play a critical role in determining the structural rearrangement and aggregation mechanism of XN1. Few experiments have studied XN1 in its entirety, with all flanking regions. To obtain structural insights into the misfolding of XN1 toward amyloid aggregation, we perform molecular dynamics simulations on monomeric XN1 with full flanking regions, a variant missing the polyproline regions, which are hypothesized to prevent aggregation, and an isolated polyQ peptide (Q(n)). For each of these three constructs, we study glutamine repeat lengths of 23, 36, 40 and 47. We find that polyQ peptides have a positive correlation between their probability to form a beta-rich misfolded state and their expansion length. We also find that the flanking regions of XN1 affect its probability to form a beta-rich state compared to the isolated polyQ. Particularly, the polyproline regions form polyproline type II helices and decrease the probability of the polyQ region to form a beta-rich state. Additionally, by lengthening polyQ, the first N-terminal 17 residues are more likely to adopt a beta-sheet conformation rather than an alpha-helix conformation. Therefore, our molecular dynamics study provides a structural insight of XN1 misfolding and elucidates the possible role of the flanking sequences in XN1 aggregation.
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