MOAG-4 promotes the aggregation of α-synuclein by competing with self-protective electrostatic interactions

Publication: Research - peer-reviewJournal article

DOI

  • Yuichi Yoshimura
    Yuichi Yoshimura
  • Mats Holmberg
    Mats Holmbergthe University of Groningen, University Medical Centre Groningen, European Research Institute for the Biology of Aging, 9700 AD Groningen, The Netherlands.Netherlands
  • Predrag Kukic
    Predrag Kukicthe Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
  • Camilla Bertel Andersen
  • Alejandro Mata-Cabana
    Alejandro Mata-Cabanathe University of Groningen, University Medical Centre Groningen, European Research Institute for the Biology of Aging, 9700 AD Groningen, The Netherlands.Netherlands
  • S. Fabio Falsone
    S. Fabio Falsonethe Institute of Pharmaceutical Sciences, University of Graz, Schubertstr. 1, 8010 Graz, Austria.Austria
  • Michele Vendruscolo
    Michele Vendruscolothe Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.United Kingdom
  • Ellen A.A. Nollen
    Ellen A.A. Nollenthe University of Groningen, University Medical Centre Groningen, European Research Institute for the Biology of Aging, 9700 AD Groningen, The Netherlands.Netherlands
  • Frans Mulder

Aberrant protein aggregation underlies a variety of age-related neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Little is known, however, about the molecular mechanisms that modulate the aggregation process in the cellular environment. Recently, MOAG-4/SERF has been identified as a class of evolutionarily conserved proteins that positively regulates aggregate formation. Here, by using nuclear magnetic resonance (NMR) spectroscopy, we examine the mechanism of action of MOAG-4 by characterizing its interaction with α-synuclein (α-Syn). NMR chemical shift perturbations demonstrate that a positively charged segment of MOAG-4 forms a transiently populated α-helix that interacts with the negatively charged C terminus of α-Syn. This process interferes with the intramolecular interactions between the N- and C-terminal regions of α-Syn, resulting in the protein populating less compact forms and aggregating more readily. These results provide a compelling example of the complex competition between molecular and cellular factors that protect against protein aggregation and those that promote it.

Original languageEnglish
JournalJournal of Biological Chemistry
Volume292
Issue number20
Pages (from-to)8269-8278
Number of pages10
ISSN0021-9258
DOIs
StatePublished - 2017

    Keywords

  • Journal Article

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