ArticleProceedings of the National Academy of Sciences of the United States of America2013
Polyglutamine domain flexibility mediates the proximity between flanking sequences in huntingtin.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
72 citing papers in PubMed, 147 citations in OpenAlex.
- Chaperone-mediated remodelling of mutant huntingtin.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2026Review
- Prevention of ubiquitination at K6 and K9 in mutant huntingtin exacerbates disease pathology in a knock-in mouse model.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Transient Interdomain Interactions Modulate the Monomeric Structural Ensemble and Self-Assembly of Huntingtin Exon 1.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- DNA Sensor ABCF1 Phase Separates With cccDNA to Inhibit Hepatitis B Virus Replication.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Evaluating AlphaFold for Clinical Pharmacology and Pharmacogenetics: A Case-Study of Huntingtin Variants Linked to Huntington's Disease.The AAPS journal · 2024Article
- Toxic effects of mutant huntingtin in axons are mediated by its proline-rich domain.Brain : a journal of neurology · 2024Article
- A clinical study and future prospects for bioactive compounds and semi-synthetic molecules in the therapies for Huntington's disease.Molecular neurobiology · 2024Review
- Visualizing multimerization of plasticity-related gene 5 at the plasma membrane using FLIM-FRET.Frontiers in molecular biosciences · 2024Article
- Amyloid modifier SERF1a interacts with polyQ-expanded huntingtin-exon 1 via helical interactions and exacerbates polyQ-induced toxicity.Communications biology · 2023Article
- Native functions of short tandem repeats.eLife · 2023Article
- The structure of pathogenic huntingtin exon 1 defines the bases of its aggregation propensity.Nature structural & molecular biology · 2023Article
- Full-length huntingtin is palmitoylated at multiple sites and post-translationally myristoylated following caspase-cleavage.Frontiers in physiology · 2023Article
- A FRET-based method for monitoring structural transitions in protein self-organization.Cell reports methods · 2022Article
- Suppression of toxicity of the mutant huntingtin protein by its interacting compound, desonide.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Recent Microscopy Advances and the Applications to Huntington's Disease Research.Journal of Huntington's disease · 2022Review
- Huntingtin structure is orchestrated by HAP40 and shows a polyglutamine expansion-specific interaction with exon 1.Communications biology · 2021Article
- Article
- Molecular mechanisms underlying nucleotide repeat expansion disorders.Nature reviews. Molecular cell biology · 2021Review
- Fluorescence-based techniques for the detection of the oligomeric status of proteins: implication in amyloidogenic diseases.European biophysics journal : EBJ · 2021Review
- Site-Specific Phosphorylation of Huntingtin Exon 1 Recombinant Proteins Enabled by the Discovery of Novel Kinases.Chembiochem : a European journal of chemical biology · 2021Article
12 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Huntington disease (HD) is a neurodegenerative disorder caused by a CAG expansion within the huntingtin gene that encodes a polymorphic glutamine tract at the amino terminus of the huntingtin protein. HD is one of nine polyglutamine expansion diseases. The clinical threshold of polyglutamine expansion for HD is near 37 repeats, but the mechanism of this pathogenic length is poorly understood. Using Förster resonance energy transfer, we describe an intramolecular proximity between the N17 domain and the downstream polyproline region that flanks the polyglutamine tract of huntingtin. Our data support the hypothesis that the polyglutamine tract can act as a flexible domain, allowing the flanking domains to come into close spatial proximity. This flexibility is impaired with expanded polyglutamine tracts, and we can detect changes in huntingtin conformation at the pathogenic threshold for HD. Altering the structure of N17, either via phosphomimicry or with small molecules, also affects the proximity between the flanking domains. The structural capacity of N17 to fold back toward distal regions within huntingtin requires an interacting protein, protein kinase C and casein kinase 2 substrate in neurons 1 (PACSIN1). This protein has the ability to bind both N17 and the polyproline region, stabilizing the interaction between these two domains. We also developed an antibody-based FRET assay that can detect conformational changes within endogenous huntingtin in wild-type versus HD fibroblasts. Therefore, we hypothesize that wild-type length polyglutamine tracts within huntingtin can form a flexible domain that is essential for proper functional intramolecular proximity, conformations, and dynamics.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.