Parkin phosphorylation and modulation of its E3 ubiquitin ligase activity

被引:99
作者
Yamamoto, A
Friedlein, A
Imai, Y
Takahashi, R
Kahle, PJ [1 ]
Haass, C
机构
[1] Univ Munich, Dept Metab Chem, Lab Alzheimer & Parkinsons Dis Res, D-80336 Munich, Germany
[2] F Hoffmann La Roche & Co Ltd, Roche Ctr Med Genom, CH-4070 Basel, Switzerland
[3] RIKEN, Brain Sci Inst, Wako, Saitama 3510198, Japan
关键词
D O I
10.1074/jbc.M407724200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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. Whereas 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 phosphoparkin. Phosphoamino acid analysis revealed that phosphorylation occurred mainly on serine residues under these conditions. At least five phosphorylation sites were identified, including Ser(101), Ser(131), and Ser(136) (located in the linker region) as well as Ser(296) and Ser(378) (located in the RING-IBR-RING motif). Casein kinase-1, protein kinase X 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 slightly but significantly elevated autoubiquitination activity. Thus, complex regulation of the phosphorylation state of parkin may contribute to the unfolded protein response in stressed cells.
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页码:3390 / 3399
页数:10
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