ArticleHuman molecular genetics2014
Association of polyalanine and polyglutamine coiled coils mediates expansion disease-related protein aggregation and dysfunction.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 73 citations in OpenAlex.
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- Divergent evolution of low-complexity regions in the vertebrate CPEB protein family.Frontiers in bioinformatics · 2025Article
- Predicting the involvement of polyQ- and polyA in protein-protein interactions by their amino acid context.Heliyon · 2024Article
- Reviewing the Structure-Function Paradigm in Polyglutamine Disorders: A Synergistic Perspective on Theoretical and Experimental Approaches.International journal of molecular sciences · 2024Review
- Alternative low-populated conformations prompt phase transitions in polyalanine repeat expansions.Nature communications · 2024Article
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- The sequence context in poly-alanine regions: structure, function and conservation.Bioinformatics (Oxford, England) · 2022Article
- Conformational dynamics in the disordered region of human CPEB3 linked to memory consolidation.BMC biology · 2022Article
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- Merging Established Mechanisms with New Insights: Condensates, Hubs, and the Regulation of RNA Polymerase II Transcription.Journal of molecular biology · 2022Review
- Heptad stereotypy, S/Q layering, and remote origin of the SARS-CoV-2 fusion core.Virus evolution · 2022Article
- Between Interactions and Aggregates: The PolyQ Balance.Genome biology and evolution · 2021Article
- PolyQ length co-evolution in neural proteins.NAR genomics and bioinformatics · 2021Article
- Structural transitions in Orb2 prion-like domain relevant for functional aggregation in memory consolidation.The Journal of biological chemistry · 2020Article
- Evolution and expansion of the RUNX2 QA repeat corresponds with the emergence of vertebrate complexity.Communications biology · 2020Review
- Cyclic Oligosaccharides as Active Drugs, an Updated Review.Pharmaceuticals (Basel, Switzerland) · 2020Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
The expansion of homopolymeric glutamine (polyQ) or alanine (polyA) repeats in certain proteins owing to genetic mutations induces protein aggregation and toxicity, causing at least 18 human diseases. PolyQ and polyA repeats can also associate in the same proteins, but the general extent of their association in proteomes is unknown. Furthermore, the structural mechanisms by which their expansion causes disease are not well understood, and these repeats are generally thought to misfold upon expansion into aggregation-prone β-sheet structures like amyloids. However, recent evidence indicates a critical role for coiled-coil (CC) structures in triggering aggregation and toxicity of polyQ-expanded proteins, raising the possibility that polyA repeats may as well form these structures, by themselves or in association with polyQ. We found through bioinformatics screenings that polyA, polyQ and polyQA repeats have a phylogenetically graded association in human and non-human proteomes and associate/overlap with CC domains. Circular dichroism and cross-linking experiments revealed that polyA repeats can form--alone or with polyQ and polyQA--CC structures that increase in stability with polyA length, forming higher-order multimers and polymers in vitro. Using structure-guided mutagenesis, we studied the relevance of polyA CCs to the in vivo aggregation and toxicity of RUNX2--a polyQ/polyA protein associated with cleidocranial dysplasia upon polyA expansion--and found that the stability of its polyQ/polyA CC controls its aggregation, localization and toxicity. These findings indicate that, like polyQ, polyA repeats form CC structures that can trigger protein aggregation and toxicity upon expansion in human genetic 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.