14-3-3η is a novel regulator of parkin ubiquitin ligase
14-3-3η is a novel regulator of parkin ubiquitin ligase
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DOI：
10.1038/sj.emboj.7600774
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发表时间：
2006-01-11
期刊：
影响因子：
11.4
通讯作者：
Tanaka, K
中科院分区：
文献类型：
--
作者：
Sato, S;Chiba, T;Tanaka, K
编码E3泛素蛋白连接酶的parkin基因的突变是常染色体隐性遗传青少年帕金森综合征（ARJP）的主要原因。虽然帕金蛋白的各种底物已被确定，但调节帕金蛋白泛素连接酶活性的机制知之甚少。在这里，我们报告，14-3-3 eta，一个伴侣样蛋白存在于神经元丰富，可以结合帕金和负调控其泛素连接酶活性。此外，14-3-3 eta可以结合帕金蛋白的连接区，但不能结合具有导致ARJP的R42 P、K161 N和T240 R突变的帕金蛋白。有趣的是，另一种家族性帕金森病（PD）基因产物α-突触核蛋白（α-SN）消除了14-3-3 eta诱导的parkin活性抑制。α-SN可与14-3-3 η紧密结合，从而将其从parkin-14 - 3 -3 η复合物中螯合。导致PD的α-SN的A30 P和A53 T突变体不能结合14-3-3 eta，并且不能激活parkin。我们的研究结果表明，14-3-3 eta是一个调节器，在功能上连接parkin和alpha-SN。parkin活性的α-SN阳性和14-3-3 eta阴性对照揭示了parkin的病理生理作用。
Mutation of the parkin gene, which encodes an E3 ubiquitin-protein ligase, is the major cause of autosomal recessive juvenile parkinsonism (ARJP). Although various substrates for parkin have been identified, the mechanisms that regulate the ubiquitin ligase activity of parkin are poorly understood. Here we report that 14-3-3 eta, a chaperone-like protein present abundantly in neurons, could bind to parkin and negatively regulate its ubiquitin ligase activity. Furthermore, 14-3-3 eta could bind to the linker region of parkin but not parkin with ARJP-causing R42P, K161N, and T240R mutations. Intriguingly, alpha-synuclein (alpha-SN), another familial Parkinson's disease (PD) gene product, abrogated the 14-3-3 eta-induced suppression of parkin activity. alpha-SN could bind tightly to 14-3-3 eta and consequently sequester it from the parkin -14-3-3 eta complex. PD-causing A30P and A53T mutants of alpha-SN could not bind 14-3-3 eta, and failed to activate parkin. Our findings indicate that 14-3-3 eta is a regulator that functionally links parkin and alpha-SN. The alpha-SN-positive and 14-3-3 eta-negative control of parkin activity sheds new light on the pathophysiological roles of parkin.