Structural disorder of monomeric α-synuclein persists in mammalian cells

Francois-Xavier Theillet, Andres Binolfi, Beata Bekei, Andrea Martorana, Honor May Rose, Marchel Stuiver, Silvia Verzini, Dorothea Lorenz, Marleen van Rossum, Daniella Goldfarb and Philipp Selenko ()
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Francois-Xavier Theillet: In-Cell NMR Laboratory, Leibniz Institute of Molecular Pharmacology (FMP Berlin)
Andres Binolfi: In-Cell NMR Laboratory, Leibniz Institute of Molecular Pharmacology (FMP Berlin)
Beata Bekei: In-Cell NMR Laboratory, Leibniz Institute of Molecular Pharmacology (FMP Berlin)
Andrea Martorana: Weizmann Institute of Science
Honor May Rose: In-Cell NMR Laboratory, Leibniz Institute of Molecular Pharmacology (FMP Berlin)
Marchel Stuiver: In-Cell NMR Laboratory, Leibniz Institute of Molecular Pharmacology (FMP Berlin)
Silvia Verzini: In-Cell NMR Laboratory, Leibniz Institute of Molecular Pharmacology (FMP Berlin)
Dorothea Lorenz: Leibniz Institute of Molecular Pharmacology (FMP Berlin)
Marleen van Rossum: In-Cell NMR Laboratory, Leibniz Institute of Molecular Pharmacology (FMP Berlin)
Daniella Goldfarb: Weizmann Institute of Science
Philipp Selenko: In-Cell NMR Laboratory, Leibniz Institute of Molecular Pharmacology (FMP Berlin)

Nature, 2016, vol. 530, issue 7588, 45-50

Abstract: Abstract Intracellular aggregation of the human amyloid protein α-synuclein is causally linked to Parkinson’s disease. While the isolated protein is intrinsically disordered, its native structure in mammalian cells is not known. Here we use nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR) spectroscopy to derive atomic-resolution insights into the structure and dynamics of α-synuclein in different mammalian cell types. We show that the disordered nature of monomeric α-synuclein is stably preserved in non-neuronal and neuronal cells. Under physiological cell conditions, α-synuclein is amino-terminally acetylated and adopts conformations that are more compact than when in buffer, with residues of the aggregation-prone non-amyloid-β component (NAC) region shielded from exposure to the cytoplasm, which presumably counteracts spontaneous aggregation. These results establish that different types of crowded intracellular environments do not inherently promote α-synuclein oligomerization and, more generally, that intrinsic structural disorder is sustainable in mammalian cells.

Date: 2016
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DOI: 10.1038/nature16531

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