Casein Kinase II-mediated Phosphorylation Regulates α -Synuclein/Synphilin-1 Interaction and Inclusion Body Formation

Gwang Lee, Mikiei Tanaka, Kiho Park, Sang Seop Lee, Yong Man Kim, Eunsung Junn, Sang Hyeon Lee, M. Maral Mouradian

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Abstract

α-Synuclein is a phosphoprotein that accumulates as a major component of Lewy bodies in the brains of patients with Parkinson disease. Synphilin-1, which is also present in Lewy bodies, binds with α-synuclein and forms cytoplasmic inclusions in transfected cells. Yet the molecular determinants of this protein-protein interaction are unknown. Here we report that casein kinase H (CKII) phosphorylates synphilin-1 and that the β subunit of this enzyme complex binds to synphilin-1. Additionally, both CKII α and β subunits are present within cytoplasmic inclusions in cells that overexpress synphilin-1. Notably, the interaction between synphilin-1 and α-synuclein is markedly dependent on phosphorylation. Inhibition of CKII activity by 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole blocks the binding between these two proteins and significantly reduces the percentage of cells that contain eosinophilic cytoplasmic inclusions. Mutation of the major CKII phosphorylation site in α-synuclein (S129A) has no significant impact on the binding between α-synuclein and synphilin-1 or on the formation of synphilin-1/α-synuclein-positive inclusions. These data suggest that the CKII-mediated phosphorylation of synphilin-1 rather than that of α-synuclein is critical in modulating their tendency to aggregate into inclusions. These observations collectively indicate that a ubiquitous post-translational modification such as phosphorylation can regulate inclusion body formation in the context of α-synuclein and synphilin-1 interaction.

Original languageEnglish (US)
Pages (from-to)6834-6839
Number of pages6
JournalJournal of Biological Chemistry
Volume279
Issue number8
DOIs
StatePublished - Feb 20 2004

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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