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

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 » 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.« less

Authors:
 [1]; ORCiD logo [2];  [3]; ORCiD logo [4];  [5]; ORCiD logo [5]; ORCiD logo [2]
+ Show Author Affiliations
  1. 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
  2. University of Nebraska Medical Center, Omaha, NE (United States). Department of Pharmaceutical Sciences
  3. University of Nebraska Medical Center, Omaha, NE (United States). Department of Pharmaceutical Sciences ; Bruker Nano Surfaces Division, Santa Barbara, CA (United States)
  4. Univ. of North Carolina, Chapel Hill, NC (United States). Curriculum in Bioinformatics and Computational Biology
  5. Univ. of North Carolina, Chapel Hill, NC (United States). Department of Biochemistry and Biophysics
Publication Date:
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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Journal Article:
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DOI:  10.1063/1.5008874
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Figures / Tables:

Figure 1 Figure 1: HS-AFM images of wild-type $\alpha$-syn monomers. Selected frames from movie S3 showing the structural transition of $\alpha$-syn monomer over time. The monomer starts in a globular conformation (0 s) and transitions to: one-tailed (13.8s, 26.0 s, 33.6 s, and 125.6 s), two-tailed (27.4 s, 62.6 s, 129.6 smore » and 132.6 s), and extended conformations (130.4 s and 136.6 s). Interspersed with the other conformations, the monomer transitions back to a globular conformation (16.8 s and 100.2 s).« less
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