Copper-zinc superoxide dismutase (Sod1) is a critical antioxidant enzyme that rids the cell of reactive oxygen through the redox cycling of a catalytic copper ion provided by its copper chaperone (Ccs). Ccs must first acquire this copper ion, directly or indirectly, from the influx copper transporter, Ctr1. The three proteins of this transport pathway ensure careful trafficking of copper ions from cell entry to target delivery, but the intricacies remain undefined. Biochemical examination of each step in the pathway determined that the activation of the target (Sod1) regulates the Ccs·Ctr1 interaction. Ccs stably interacts with the cytosolic C-terminal tail of Ctr1 (Ctr1c) in a copper-dependent manner. This interaction becomes tripartite upon the addition of an engineered immature form of Sod1 creating a stable Cu(I)-Ctr1c·Ccs·Sod1 heterotrimer in solution. This heterotrimer can also be made by the addition of a preformed Sod1·Ccs heterodimer to Cu(I)-Ctr1c, suggestive of multiple routes to the same destination. Only complete Sod1 activation (i.e. active site copper delivery and intra-subunit disulfide bond formation) breaks the Sod1·Ccs·Ctr1c complex. The results provide a new and extended view of the Sod1 activation pathway(s) originating at cellular copper import.

中文翻译：

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铜锌超氧化物歧化酶 (Sod1) 激活会终止其铜伴侣 (Ccs) 与铜输入蛋白 Ctr1 的胞质金属结合域之间的相互作用。


铜锌超氧化物歧化酶 (Sod1) 是一种重要的抗氧化酶，可通过铜伴侣 (Ccs) 提供的催化铜离子的氧化还原循环消除细胞中的活性氧。 Ccs 必须首先从流入的铜转运蛋白 Ctr1 直接或间接获取这种铜离子。该运输途径的三种蛋白质确保铜离子从细胞进入到目标递送的小心运输，但其复杂性仍不清楚。对通路中每个步骤的生化检查确定靶标 (Sod1) 的激活调节 Ccs·Ctr1 相互作用。 Ccs 以铜依赖性方式与 Ctr1 (Ctr1c) 的胞质 C 末端尾部稳定地相互作用。添加工程化的未成熟形式的 Sod1 后，这种相互作用变成三方，在溶液中形成稳定的 Cu(I)-Ctr1c·Ccs·Sod1 异三聚体。这种异源三聚体也可以通过将预先形成的 Sod1·Ccs 异源二聚体添加到 Cu(I)-Ctr1c 上来制备，这表明通往同一目的地的多种路线。只有完全的 Sod1 激活（即活性位点铜传递和亚基内二硫键形成）才能破坏 Sod1·Ccs·Ctr1c 复合物。这些结果为起源于细胞铜输入的 Sod1 激活途径提供了新的、扩展的视角。