MOAG-4 promotes the aggregation of α-synuclein by competing with self-protective electrostatic interactions.
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.
Interdisciplinary Nanoscience Center (iNANO) and Department of Chemistry, Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C, Denmark.
Yuichi
Y
Yoshimura
University of Groningen, University Medical Centre Groningen, European Research Institute for the Biology of Aging, 9700 AD Groningen, The Netherlands.
Mats A
MA
Holmberg
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
Predrag
P
Kukic
Interdisciplinary Nanoscience Center (iNANO) and Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C, Denmark.
Camilla B
CB
Andersen
University of Groningen, University Medical Centre Groningen, European Research Institute for the Biology of Aging, 9700 AD Groningen, The Netherlands.
Alejandro
A
Mata-Cabana
Institute of Pharmaceutical Sciences, University of Graz, Schubertstr. 1, 8010 Graz, Austria.
S Fabio
SF
Falsone
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
Michele
M
Vendruscolo
University of Groningen, University Medical Centre Groningen, European Research Institute for the Biology of Aging, 9700 AD Groningen, The Netherlands.
Ellen A A
EAA
Nollen
Interdisciplinary Nanoscience Center (iNANO) and Department of Chemistry, Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C, Denmark. Electronic address: fmulder@chem.au.dk.
Frans A A
FAA
Mulder
D000544:Alzheimer Disease; D000818:Animals; D017173:Caenorhabditis elegans / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010300:Parkinson Disease; D066329:Protein Aggregates; D055672:Static Electricity; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D029742:Caenorhabditis elegans Proteins; C552054:MOAG-4 protein, C elegans; D009419:Nerve Tissue Proteins; D066329:Protein Aggregates; D051844:alpha-Synuclein
neurodegenerative disease; nuclear magnetic resonance (NMR); protein aggregation; protein structure; α-synuclein (α-synuclein)