ArticleThe Journal of biological chemistry2017
A pH-dependent switch promotes β-synuclein fibril formation via glutamate residues.
Article in The Journal of biological chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 43 citations in OpenAlex.
- Is synuclein aggregation a derived or ancestral trait? Ancestral sequence reconstruction uncovers stepwise evolution of synuclein aggregation.bioRxiv : the preprint server for biology · 2025Article
- Subtle concentration changes in zinc hold the key to fibrillation of α-synuclein: an updated insight on the micronutrient's role in prevention of neurodegenerative disorders.Frontiers in molecular biosciences · 2025Review
- Substitution of Met-38 to Ile in γ-synuclein found in two patients with amyotrophic lateral sclerosis induces aggregation into amyloid.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- An ankyrin repeat chaperone targets toxic oligomers during amyloidogenesis.Protein science : a publication of the Protein Society · 2023Article
- Multifaceted interactions mediated by intrinsically disordered regions play key roles in alpha synuclein aggregation.Current opinion in structural biology · 2023Review
- Age-Related Changes of the Synucleins Profile in the Mouse Retina.Biomolecules · 2023Article
- β-Synuclein: An Enigmatic Protein with Diverse Functionality.Biomolecules · 2022Review
- Synuclein Family Members Prevent Membrane Damage by Counteracting α-Synuclein Aggregation.Biomolecules · 2021Article
- A pH-eQTL Interaction at theFrontiers in aging neuroscience · 2021Article
- Metal ions shape α-synuclein.Scientific reports · 2020Article
- Amyloidogenic Propensities of Ribosomal S1 Proteins: Bioinformatics Screening and Experimental Checking.International journal of molecular sciences · 2020Article
- Antioxidant Nanoparticles for Concerted Inhibition of α-Synuclein Fibrillization, and Attenuation of Microglial Intracellular Aggregation and Activation.Frontiers in bioengineering and biotechnology · 2020Article
- Increased Dynamics of α-Synuclein Fibrils by β-Synuclein Leads to Reduced Seeding and Cytotoxicity.Scientific reports · 2019Article
- pH-Dependent fibril maturation of a Pmel17 repeat domain isoform revealed by tryptophan fluorescence.Biochimica et biophysica acta. Proteins and proteomics · 2019Article
- Investigating the neuroprotective effect of AAV-mediated β-synuclein overexpression in a transgenic model of synucleinopathy.Scientific reports · 2018Article
- Interactions between the Intrinsically Disordered Proteins β-Synuclein and α-Synuclein.Proteomics · 2018Review
- Multi-Pronged Interactions Underlie Inhibition of α-Synuclein Aggregation by β-Synuclein.Journal of molecular biology · 2018Article
- Alternative Splicing of Alpha- and Beta-Synuclein Genes Plays Differential Roles in Synucleinopathies.Genes · 2018Review
- Sumoylation Protects Against β-Synuclein Toxicity in Yeast.Frontiers in molecular neuroscience · 2018Article
- Getting in charge of β-synuclein fibrillation.The Journal of biological chemistry · 2017Article
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6 authors at 1 institution in 1 country.
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Abstract
α-Synuclein (αS) is the primary protein associated with Parkinson's disease, and it undergoes aggregation from its intrinsically disordered monomeric form to a cross-β fibrillar form. The closely related homolog β-synuclein (βS) is essentially fibril-resistant under cytoplasmic physiological conditions. Toxic gain-of-function by βS has been linked to dysfunction, but the aggregation behavior of βS under altered pH is not well-understood. In this work, we compare fibril formation of αS and βS at pH 7.3 and mildly acidic pH 5.8, and we demonstrate that pH serves as an on/off switch for βS fibrillation. Using αS/βS domain-swapped chimera constructs and single residue substitutions in βS, we localized the switch to acidic residues in the N-terminal and non-amyloid component domains of βS. Computational models of βS fibril structures indicate that key glutamate residues (Glu-31 and Glu-61) in these domains may be sites of pH-sensitive interactions, and variants E31A and E61A show dramatically altered pH sensitivity for fibril formation supporting the importance of these charged side chains in fibril formation of βS. Our results demonstrate that relatively small changes in pH, which occur frequently in the cytoplasm and in secretory pathways, may induce the formation of βS fibrils and suggest a complex role for βS in synuclein cellular homeostasis and Parkinson's disease.
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