α-Synuclein misfolding assessed with single molecule AFM force spectroscopy: effect of pathogenic mutations
| Autor: | Jean-Christophe Rochet, Ivan L. Volkov, Yuri L. Lyubchenko, Josephat M. Asiago, Jagadish Hindupur, Alexey V. Krasnoslobodtsev |
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| Rok vydání: | 2013 |
| Předmět: |
Protein Folding
Protein Conformation Dimer Microscopy Atomic Force Biochemistry Article law.invention chemistry.chemical_compound Protein structure law Molecule Humans Point Mutation Alpha-synuclein Chemistry Point mutation Force spectroscopy Parkinson Disease Recombinant Proteins Kinetics Recombinant DNA Biophysics Mutagenesis Site-Directed alpha-Synuclein Protein folding Protein Multimerization |
| Zdroj: | Biochemistry. 52(42) |
| ISSN: | 1520-4995 |
| Popis: | Misfolding and subsequent aggregation of alpha-synuclein (α-Syn) protein are critically involved in the development of several neurodegenerative diseases, including Parkinson’s disease (PD). Three familial single point mutations, A30P, E46K, and A53T, correlate with early-onset PD; however the molecular mechanism of the effects of these mutations on the structural properties of α-Syn and its propensity to misfold remains unclear. Here, we address this issue utilizing a single molecule AFM force spectroscopy approach in which structural details of dimers formed by all four variants of α-Syn are characterized. Analysis of the force spectroscopy data reflecting contour length distribution for α-Syn dimer dissociation suggests that multiple segments are involved in the assembly of the dimer. The interactions are not limited to the central non-amyloid-beta component (NAC) of the protein, but rather expand beyond this segment. All three mutations alter the protein’s folding and interaction patterns affecting interactions far beyond their immediate locations. Implementation of these findings to our understanding of α-Syn aggregation pathways is discussed. |
| Databáze: | OpenAIRE |
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