The copper chaperone CCS directly interacts with copper/zinc superoxide dismutase
The copper chaperone CCS directly interacts with copper/zinc superoxide dismutase
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DOI：
10.1074/jbc.273.37.23625
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发表时间：
1998-09-11
影响因子：
4.8
通讯作者：
Gitlin, JD
中科院分区：
文献类型：
--
作者：
Casareno, RLB;Waggoner, D;Gitlin, JD
编码铜/锌超氧化物歧化酶 (SOD1) 的基因中的显性遗传突变会导致致命的运动神经元疾病家族性肌萎缩侧索硬化症 (FALS)。这些突变使 SOD1 获得功能，并由于突变酶中铜的自由基生成活性增强而导致神经元变性。铜向 SOD1 的传递是通过可溶性因子介导的，该因子被确定为 SOD1 的铜伴侣 (CCS)。 SOD1 和 CCS 的氨基酸序列比对揭示了与介导 SOD1 同二聚化所必需的氨基酸的保守性惊人的同源性。在这里，我们证明 CCS 和 SOD1 在体外和体内直接相互作用，并且这种相互作用是通过每种蛋白质中的同源结构域介导的。重要的是，CCS 不仅与野生型 SOD1 相互作用，还与含有常见错义突变的 SOD1 相互作用，导致 FALS。因此，我们的研究结果揭示了不同 SOD1 FALS 突变体可能导致神经元损伤的共同机制，并为受这种致命疾病影响的患者提出了一种新的治疗方法。
Dominantly inherited mutations in the gene encoding copper/zinc superoxide dismutase (SOD1) result in the fatal motor neuron disease familial amyotrophic lateral sclerosis (FALS), These mutations confer a gain-of-function to SOD1 with neuronal degeneration resulting from enhanced free radical generating activity of the copper present in the mutant enzyme. The delivery of copper to SOD1 is mediated through a soluble factor identified as the copper chaperone for SOD1 (CCS). Amino acid sequence alignment of SOD1 and CCS reveals a striking homology with conservation of the amino acids essential for mediating SOD1 homodimerization. Here we demonstrate that CCS and SOD1 directly interact in vitro and in vivo and that this interaction is mediated via the homologous domains in each protein. Importantly, CCS interacts not only with wild-type SOD1 but also with SOD1 containing the common missense mutations resulting in FALS. Our findings therefore reveal a common mechanism whereby different SOD1 FALS mutants may result in neuronal injury and suggest a novel therapeutic approach in patients affected by this fatal disease.