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Papers In Press, published online ahead of print November 22, 2004
Ludwig Maximilians University, Munich 80336
Corresponding Author: Philipp.Kahle{at}med.uni-muenchen.de
Mutations in the PARKIN gene are the most common cause of hereditary parkinsonism. The parkin protein comprises an N-terminal ubiquitin-like domain, a linker region containing caspase cleavage sites, a unique domain in the central portion and a special zinc finger configuration termed RING-IBR-RING. Parkin has E3 ubiquitin-protein ligase activity and is believed to mediate proteasomal degradation of aggregation-prone proteins. While the effects of mutations on the structure and function of parkin have been intensely studied, post-translational modifications of parkin and the regulation of its enzymatic activity are poorly understood. Here we report that parkin is phosphorylated both in human embryonic kidney HEK293 cells and human neuroblastoma SH-SY5Y cells. The turnover of parkin phosphorylation was rapid, because inhibition of phosphatases with okadaic acid was necessary to stabilize phospho-parkin. Phosphoamino acid analysis revealed that phosphorylation occurred mainly on serine residues under these conditions. At least five phosphorylation sites were identified, including S101, S131, S136 (located in the linker region) as well as S296 and S378 (located in the RING-IBR-RING motif). Casein kinase-1, protein kinase A and protein kinase C phosphorylated parkin in vitro, and inhibition of casein kinase-1 caused a dramatic reduction of parkin phosphorylation in cell lysates. Induction of protein folding stress in cells reduced parkin phosphorylation, and unphosphorylated parkin had a small but significant reduction in auto-ubiquitination activity. Thus, complex regulation of the phosphorylation state of parkin may contribute to the unfolded protein response in stressed cells.
J. Biol. Chem, 10.1074/jbc.M407724200
Submitted on July 9, 2004
Revised on November 12, 2004
Accepted on November 22, 2004
Parkin phosphorylation and modulation of its E3 ubiquitin ligase activity
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