Autoregulation of Parkin activity through its ubiquitin-like domain
Autoregulation of Parkin activity through its ubiquitin-like domain
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DOI：
10.1038/emboj.2011.204
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发表时间：
2011-07-20
期刊：
影响因子：
11.4
通讯作者：
Walden, Helen
中科院分区：
文献类型：
--
作者：
Chaugule, Viduth K.;Burchell, Lynn;Walden, Helen
Parkin是属于RBR（RING-InBetweenRING-RING家族）的E3-泛素连接酶，并且参与神经退行性疾病帕金森病。常染色体隐性遗传的青少年帕金森综合征是最常见的家族性帕金森病之一，与parkin基因突变直接相关。然而，疾病状态下帕金功能障碍的分子机制仍有待建立。我们现在证明，帕金蛋白的泛素样结构域的功能，以抑制其autoubiquitination。此外，致病性帕金突变破坏这种自抑制，导致组成型活性分子。此外，我们表明，自动调节的机制涉及泛素结合的C-末端区域的帕金。我们的观察提供了重要的分子洞察帕金森氏病的基础，并在调节RBR E3连接酶的活性。The EMBO Journal（2011）30，2853-2867. doi：10.1038/daj.2011.204; 2011年6月21日在线发布
Parkin is an E3-ubiquitin ligase belonging to the RBR (RING-InBetweenRING-RING family), and is involved in the neurodegenerative disorder Parkinson's disease. Autosomal recessive juvenile Parkinsonism, which is one of the most common familial forms of the disease, is directly linked to mutations in the parkin gene. However, the molecular mechanisms of Parkin dysfunction in the disease state remain to be established. We now demonstrate that the ubiquitin-like domain of Parkin functions to inhibit its autoubiquitination. Moreover pathogenic Parkin mutations disrupt this autoinhibition, resulting in a constitutively active molecule. In addition, we show that the mechanism of autoregulation involves ubiquitin binding by a C-terminal region of Parkin. Our observations provide important molecular insights into the underlying basis of Parkinson's disease, and in the regulation of RBR E3-ligase activity. The EMBO Journal ( 2011) 30, 2853-2867. doi:10.1038/emboj.2011.204; Published online 21 June 2011