Parkin functions as an E2-dependent ubiquitin-protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1
Parkin functions as an E2-dependent ubiquitin-protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1
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DOI：
10.1073/pnas.240347797
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发表时间：
2000-11-21
影响因子：
11.1
通讯作者：
Dawson, TM
中科院分区：
文献类型：
--
作者：
Zhang, Y;Gao, J;Dawson, TM
帕金森病是一种常见的神经退行性疾病，家族相关基因为这种疾病的发病机制提供了新的见解。帕金蛋白是一种功能未知的含无名指蛋白，其突变与常染色体隐性家族性帕金森氏病的发病机制有关。在这里，我们发现Parkin通过其c端无名指与E2泛素偶联人酶8 （UbcH8）结合。在UbcH8存在下，Parkin具有泛素蛋白连接酶活性。帕金也使自身泛素化并促进自身降解。我们还发现突触囊泡相关蛋白CDCrel-1通过其环指结构域与Parkin相互作用。此外，Parkin泛素化并促进CDCrel-1的降解。家族连锁突变破坏Parkin的泛素蛋白连接酶功能，损害Parkin和CDCrel-1的降解。这些结果表明，Parkin通过其环结构域作为E3泛素蛋白连接酶起作用，并可能通过泛素化控制蛋白水平。家族连锁突变中帕金森氏泛素蛋白连接酶功能的丧失表明这可能是家族性常染色体隐性帕金森氏病的原因。
Parkinson's disease is a common neurodegenerative disorder in which familial-linked genes have provided novel insights into the pathogenesis of this disorder. Mutations in Parkin, a ring-finger-containing protein of unknown function, are implicated in the pathogenesis of autosomal recessive familial Parkinson's disease. Here, we show that Parkin binds to the E2 ubiquitin-conjugating human enzyme 8 (UbcH8) through its C-terminal ring-finger. Parkin has ubiquitin-protein ligase activity in the presence of UbcH8. Parkin also ubiquitinates itself and promotes its own degradation. We also identify and show that the synaptic vesicle-associated protein, CDCrel-1, interacts with Parkin through its ring-finger domains. Furthermore, Parkin ubiquitinates and promotes the degradation of CDCrel-1. Familial-linked mutations disrupt the ubiquitin-protein ligase function of Parkin and impair Parkin and CDCrel-1 degradation. These results suggest that Parkin functions as an E3 ubiquitin-protein ligase through its ring domains and that it may control protein levels via ubiquitination. The loss of Parkin's ubiquitin-protein ligase function in familial-linked mutations suggests that this may be the cause of familial autosomal recessive Parkinson's disease.