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

Yuliang Zhang, Mohtadin Hashemi, Zhengjian Lv, Benfeard Williams, Konstantin I. Popov, Nikolay V. Dokholyan, Yuri L Lyubchenko

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number123322
JournalJournal of Chemical Physics
Volume148
Issue number12
DOIs
StatePublished - Mar 28 2018

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Synucleins
dynamic structural analysis
Structural dynamics
Dimers
Atomic force microscopy
monomers
Monomers
dimers
high speed
atomic force microscopy
Parkinson disease
Conformations
Molecular dynamics
molecular dynamics
hinges
Computer simulation
Hinges
oligomers
Oligomers
helices

ASJC Scopus subject areas

  • Physics and Astronomy(all)
  • Physical and Theoretical Chemistry

Cite this

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

In: Journal of Chemical Physics, Vol. 148, No. 12, 123322, 28.03.2018.

Research output: Contribution to journalArticle

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. In: Journal of Chemical Physics. 2018 ; Vol. 148, No. 12.
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