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

Yoshimura, Y., Holmberg, M. A., Kukic, P., Andersen, C. B., Mata-Cabana, A., Falsone, S. F., Vendruscolo, M., Nollen, E. A. A. & Mulder, F. A. A., 19-May-2017, In : The Journal of Biological Chemistry. 292, 20, p. 8269-8278 10 p.

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  • J. Biol. Chem.-2017-Yoshimura-8269-78

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DOI

  • Yuichi Yoshimura
  • Mats A Holmberg
  • Predrag Kukic
  • Camilla B Andersen
  • Alejandro Mata-Cabana
  • S Fabio Falsone
  • Michele Vendruscolo
  • Ellen A A Nollen
  • Frans A A 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 (αSyn). 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 αSyn. This process interferes with the intra-molecular interactions between the N- and C-terminal regions of αSyn, 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
Pages (from-to)8269-8278
Number of pages10
JournalThe Journal of Biological Chemistry
Volume292
Issue number20
Publication statusPublished - 19-May-2017

    Keywords

  • TRIPLE-RESONANCE EXPERIMENTS, FIBRIL FORMATION, NMR EXPERIMENTS, AMYLOID FIBRILS, CHEMICAL-SHIFTS, IMPROVED SENSITIVITY, DISORDERED PROTEINS, LIGAND-BINDING, PRION PROTEIN, KINETICS

ID: 40770410