Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 292, Issue 20, Pages 8269-8278Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M116.764886
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Funding
- European Molecular Biology Organization Long-term Fellowship [ALTF 687-2013]
- Marie Curie Actions Fellowship
- European Research Council
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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 alpha-synuclein (alpha-Syn). NMR chemical shift perturbations demonstrate that a positively charged segment of MOAG-4 forms a transiently populated alpha-helix that interacts with the negatively charged C terminus of alpha-Syn. This process interferes with the intramolecular interactions between the Nand C-terminal regions of alpha-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.
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