High-speed atomic force microscopy reveals structural dynamics of α-synuclein monomers and dimers
Autor: | Yuri L. Lyubchenko, Benfeard Williams, Yuliang Zhang, Konstantin I. Popov, Mohtadin Hashemi, Zhengjian Lv, Nikolay V. Dokholyan |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Dimer Molecular Conformation General Physics and Astronomy Molecular Dynamics Simulation 010402 general chemistry Fibril Microscopy Atomic Force 01 natural sciences 03 medical and health sciences chemistry.chemical_compound Molecular dynamics Special Topic: Single Molecule Biophysics Physical and Theoretical Chemistry Aqueous solution Molecular biophysics 0104 chemical sciences 030104 developmental biology Monomer chemistry Biophysics alpha-Synuclein Dumbbell Self-assembly Dimerization Hydrophobic and Hydrophilic Interactions |
Popis: | α-Synuclein (α-syn) is the major component of the intraneuronal inclusions called Lewy bodies, which are the pathological hallmark of Parkinson's disease. α-Syn is capable of self-assembly into many different species, such as soluble oligomers and fibrils. Even though attempts to resolve the structures of the protein have been made, detailed understanding about the structures and their relationship with the different aggregation steps is lacking, which is of interest to provide insights into the pathogenic mechanism of Parkinson's disease. Here we report the structural flexibility of α-syn monomers and dimers in an aqueous solution environment as probed by single-molecule time-lapse high-speed AFM. In addition, we present the molecular basis for the structural transitions using discrete molecular dynamics (DMD) simulations. α-Syn monomers assume a globular conformation, which is capable of forming tail-like protrusions over dozens of seconds. Importantly, a globular monomer can adopt fully extended conformations. Dimers, on the other hand, are less dynamic and show a dumbbell conformation that experiences morphological changes over time. DMD simulations revealed that the α-syn monomer consists of several tightly packed small helices. The tail-like protrusions are also helical with a small β-sheet, acting as a "hinge". Monomers within dimers have a large interfacial interaction area and are stabilized by interactions in the non-amyloid central (NAC) regions. Furthermore, the dimer NAC-region of each α-syn monomer forms a β-rich segment. Moreover, NAC-regions are located in the hydrophobic core of the dimer. |
Databáze: | OpenAIRE |
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