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

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

OriginalsprogEngelsk
TidsskriftJournal of Biological Chemistry
Vol/bind292
Nummer20
Sider (fra-til)8269-8278
Antal sider10
ISSN0021-9258
DOI
StatusUdgivet - 2017

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