ArticleeLife2023
Pathologic polyglutamine aggregation begins with a self-poisoning polymer crystal.
Article in eLife, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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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.
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Who cites it
21 citing papers in PubMed.
- Article
- Multiscale Simulations Elucidate the Mechanism of Polyglutamine Aggregation and the Role of Flanking Domains in Fibril Polymorphism.The journal of physical chemistry. B · 2025Article
- A Coarse-Grained MD Model for Disorder-To-Order Transitions in PolyQ Aggregation.Journal of chemical theory and computation · 2025Article
- Transient Interdomain Interactions Modulate the Monomeric Structural Ensemble and Self-Assembly of Huntingtin Exon 1.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- A tool to dissect heterotypic determinants of homotypic protein phase behavior.Protein science : a publication of the Protein Society · 2025Article
- Multiscale simulations elucidate the mechanism of polyglutamine aggregation and the role of flanking domains in fibril polymorphism.bioRxiv : the preprint server for biology · 2025Article
- Inhibitor-based modulation of huntingtin aggregation mechanisms mitigates fibril-induced cellular stress.Nature communications · 2025Article
- Review
- The role of nucleation in sickle cell pathophysiology: opportunities for innovative treatments.Annals of medicine and surgery (2012) · 2025Review
- A tunable affinity fusion tag for protein self-assembly.bioRxiv : the preprint server for biology · 2025Article
- A tool to dissect heterotypic determinants of homotypic protein phase behavior.bioRxiv : the preprint server for biology · 2025Article
- Investigating the Aggregation and Prionogenic Properties of Human Cancer-Related Proteins.Molecular and cellular biology · 2025Article
- Integrative determination of atomic structure of mutant huntingtin exon 1 fibrils implicated in Huntington disease.Nature communications · 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
- Polyglutamine (PolyQ) Diseases: Navigating the Landscape of Neurodegeneration.ACS chemical neuroscience · 2024Review
- Reviewing the Structure-Function Paradigm in Polyglutamine Disorders: A Synergistic Perspective on Theoretical and Experimental Approaches.International journal of molecular sciences · 2024Review
- Solid-state nuclear magnetic resonance in the structural study of polyglutamine aggregation.Biochemical Society transactions · 2024Review
- Quantitative Model of Multiple Crystal Growth Rate Minima in Polymers with Regularly Spaced Substituent Groups.Macromolecules · 2024Article
- Photocontrol of the β-Hairpin Polypeptide Structure through an Optimized Azobenzene-Based Amino Acid Analogue.Journal of the American Chemical Society · 2024Article
- Amyloid, Crohn's disease, and Alzheimer's disease - are they linked?Frontiers in cellular and infection microbiology · 2024Review
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14 authors.
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Abstract
A long-standing goal of amyloid research has been to characterize the structural basis of the rate-determining nucleating event. However, the ephemeral nature of nucleation has made this goal unachievable with existing biochemistry, structural biology, and computational approaches. Here, we addressed that limitation for polyglutamine (polyQ), a polypeptide sequence that causes Huntington's and other amyloid-associated neurodegenerative diseases when its length exceeds a characteristic threshold. To identify essential features of the polyQ amyloid nucleus, we used a direct intracellular reporter of self-association to quantify frequencies of amyloid appearance as a function of concentration, conformational templates, and rational polyQ sequence permutations. We found that nucleation of pathologically expanded polyQ involves segments of three glutamine (Q) residues at every other position. We demonstrate using molecular simulations that this pattern encodes a four-stranded steric zipper with interdigitated Q side chains. Once formed, the zipper poisoned its own growth by engaging naive polypeptides on orthogonal faces, in a fashion characteristic of polymer crystals with intramolecular nuclei. We further show that self-poisoning can be exploited to block amyloid formation, by genetically oligomerizing polyQ prior to nucleation. By uncovering the physical nature of the rate-limiting event for polyQ aggregation in cells, our findings elucidate the molecular etiology of polyQ diseases.
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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.