High-speed atomic force microscopy reveals structural dynamics of α-synuclein monomers and dimers

doi:10.1063/1.5008874

Title: High-speed atomic force microscopy reveals structural dynamics of α-synuclein monomers and dimers

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Abstract

We report that 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 largemore »« less

Authors:

Zhang, Yuliang ^[1];

^[2]; Lv, Zhengjian ^[3];

^[4]; Popov, Konstantin I. ^[5];

^[5];

^[2]

University of Nebraska Medical Center, Omaha, NE (United States). Department of Pharmaceutical Sciences; Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Biology and Biotechnology Division, Physical and Life Sciences Directorate
University of Nebraska Medical Center, Omaha, NE (United States). Department of Pharmaceutical Sciences
University of Nebraska Medical Center, Omaha, NE (United States). Department of Pharmaceutical Sciences ; Bruker Nano Surfaces Division, Santa Barbara, CA (United States)
Univ. of North Carolina, Chapel Hill, NC (United States). Curriculum in Bioinformatics and Computational Biology
Univ. of North Carolina, Chapel Hill, NC (United States). Department of Biochemistry and Biophysics

Publication Date:: 2018-01-11

Research Org.:: Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

Sponsoring Org.:: USDOE National Nuclear Security Administration (NNSA)

OSTI Identifier:: 1458666

Report Number(s):: LLNL-JRNL-743994
Journal ID: ISSN 0021-9606; 898957; TRN: US1901496

Grant/Contract Number:: AC52-07NA27344

Resource Type:: Accepted Manuscript

Journal Name:: Journal of Chemical Physics

Additional Journal Information:: Journal Volume: 148; Journal Issue: 12; Journal ID: ISSN 0021-9606

Publisher:: American Institute of Physics (AIP)

Country of Publication:: United States

Language:: English

Subject:: 59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Atomic force microscopy; Polymers; Peptides; Thermodynamic properties; Diseases and conditions; Molecular dynamics; Biomolecules; Computational models; Lipids

Citation Formats


                    Zhang, Yuliang, Hashemi, Mohtadin, Lv, Zhengjian, Williams, Benfeard, Popov, Konstantin I., Dokholyan, Nikolay V., and Lyubchenko, Yuri L. High-speed atomic force microscopy reveals structural dynamics of α-synuclein monomers and dimers.  United States: N. p., 2018. 
        Web.  doi:10.1063/1.5008874.

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                    Zhang, Yuliang, Hashemi, Mohtadin, Lv, Zhengjian, Williams, Benfeard, Popov, Konstantin I., Dokholyan, Nikolay V., & Lyubchenko, Yuri L. High-speed atomic force microscopy reveals structural dynamics of α-synuclein monomers and dimers.  United States.  doi:10.1063/1.5008874.

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                    Zhang, Yuliang, Hashemi, Mohtadin, Lv, Zhengjian, Williams, Benfeard, Popov, Konstantin I., Dokholyan, Nikolay V., and Lyubchenko, Yuri L. Thu .  
        "High-speed atomic force microscopy reveals structural dynamics of α-synuclein monomers and dimers".  United States.  doi:10.1063/1.5008874.  https://www.osti.gov/servlets/purl/1458666.

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@article{osti_1458666,

  title        = {High-speed atomic force microscopy reveals structural dynamics of α-synuclein monomers and dimers},

  author       = {Zhang, Yuliang and Hashemi, Mohtadin and Lv, Zhengjian and Williams, Benfeard and Popov, Konstantin I. and Dokholyan, Nikolay V. and Lyubchenko, Yuri L.},

  abstractNote = {We report that 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. Additionally, 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.},

  doi          = {10.1063/1.5008874},

  journal      = {Journal of Chemical Physics},

  number       = 12,

  volume       = 148,

  place        = {United States},

  year         = {2018},

  month        = {1}

}

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DOI: 10.1063/1.5008874

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