Phosphorylation at Ser-129 but not the phosphomimics S129E/D inhibits the fibrillation of α-synuclein

Katerina E. Paleologou, Adrian W. Schmid, Carla C. Rospigliosi, Hai Young Kim, Gonzalo R. Lamberto, Ross A. Fredenburg, Peter T. Lansbury, Claudio O. Fernandez, David Eliezer, Markus Zweckstetter, Hilal A. Lashuel

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Abstract

α-Synuclein (α-syn) phosphorylation at serine 129 is characteristic of Parkinson disease (PD) and related α-synulceinopathies. However, whether phosphorylation promotes or inhibits α-syn aggregation and neurotoxicity in vivo remains unknown. This understanding is critical for elucidating the role of α-syn in the pathogenesis of PD and for development of therapeutic strategies for PD. To better understand the structural and molecular consequences of Ser-129 phosphorylation, we compared the biochemical, structural, and membrane binding properties of wild type α-syn to those of the phosphorylation mimics (S129E, S129D) as well as of in vitro phosphorylated α-syn using a battery of biophysical techniques. Our results demonstrate that phosphorylation at Ser-129 increases the conformational flexibility of α-syn and inhibits its fibrillogenesis in vitro but does not perturb its membrane-bound conformation. In addition, we show that the phosphorylation mimics (S129E/D) do not reproduce the effect of phosphorylation on the structural and aggregation properties of α-syn in vitro. Our findings have significant implications for current strategies to elucidate the role of phosphorylation in modulating protein structure and function in health and disease and provide novel insight into the underlying mechanisms that govern α-syn aggregation and toxicity in PD and related α-synulceinopathies.

Original languageEnglish
Pages (from-to)16895-16905
Number of pages11
JournalJournal of Biological Chemistry
Volume283
Issue number24
DOIs
Publication statusPublished - 13 Jun 2008
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Paleologou, K. E., Schmid, A. W., Rospigliosi, C. C., Kim, H. Y., Lamberto, G. R., Fredenburg, R. A., Lansbury, P. T., Fernandez, C. O., Eliezer, D., Zweckstetter, M., & Lashuel, H. A. (2008). Phosphorylation at Ser-129 but not the phosphomimics S129E/D inhibits the fibrillation of α-synuclein. Journal of Biological Chemistry, 283(24), 16895-16905. https://doi.org/10.1074/jbc.M800747200