ArticleThe journal of physical chemistry. B2015
Effects of Mutations on the Reconfiguration Rate of α-Synuclein.
Article in The journal of physical chemistry. B, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 16 citations in OpenAlex.
- O-GlcNAc Modification of α-Synuclein Can Alter Monomer Dynamics to Control Aggregation Kinetics.ACS chemical neuroscience · 2024Article
- Characterization of Amyloidogenic Peptide Aggregability in Helical Subspace.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Predicting and Simulating Mutational Effects on Protein Folding Kinetics.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Roles, Characteristics, and Analysis of Intrinsically Disordered Proteins: A Minireview.Life (Basel, Switzerland) · 2020Review
- Spontaneous Switching among Conformational Ensembles in Intrinsically Disordered Proteins.Biomolecules · 2019Review
- Living in Promiscuity: The Multiple Partners of Alpha-Synuclein at the Synapse in Physiology and Pathology.International journal of molecular sciences · 2019Review
- Intramolecular Diffusion in α-Synuclein: It Depends on How You Measure It.Biophysical journal · 2018Article
- Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric form.Neurobiology of disease · 2017Article
- Prion protein dynamics before aggregation.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Looking at the recent advances in understanding α-synuclein and its aggregation through the proteoform prism.F1000Research · 2017Review
- Intramolecular diffusion controls aggregation of the PAPf39 peptide.Biophysical chemistry · 2016Article
- Direct Observation of the Intrinsic Backbone Torsional Mobility of Disordered Proteins.Biophysical journal · 2016Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
It is still poorly understood why α-synuclein, the intrinsically disordered protein involved in Parkinson's and other neurodegenerative diseases, is so prone to aggregation. Recent work has shown a correlation between the aggregation rate and the rate of diffusional reconfiguration by varying temperature and pH. Here we examine the effects of several point mutations in the sequence on the conformational ensemble and reconfiguration rate. We find that at lower temperatures the PD causing aggregation enhancing mutations slow down and aggregation reducing mutations drastically speed up intramolecular diffusion, as compared to the wild type sequence. However, at higher temperatures, one of three familial mutations that enhance aggregation slows intramolecular diffusion while non-natural mutations that inhibit aggregation speed up intramolecular diffusion. These results support the hypothesis that the first step of aggregation is kinetically controlled by reconfiguration in which the protein chain cannot reconfigure rapidly enough to escape oligomerization. Finally we provide physical and chemical insights into why small point mutations cause these dramatic changes in the conformational ensemble and dynamics.
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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.