Crystal structure of the second domain of the human copper chaperone for superoxide dismutase
Crystal structure of the second domain of the human copper chaperone for superoxide dismutase
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DOI：
10.1021/bi992822i
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发表时间：
2000-02-22
期刊：
影响因子：
2.9
通讯作者：
Rosenzweig, AC
中科院分区：
文献类型：
--
作者：
Lamb, AL;Wernimont, AK;Rosenzweig, AC
超氧化物歧化酶 (hCCS) 的人铜伴侣将必需的铜离子辅助因子传递给铜、锌超氧化物歧化酶 (SOD1)，这是抗氧化防御的关键酶。 SOD1 突变与家族性肌萎缩侧索硬化症 (FALS) 有关，这是一种致命的神经退行性疾病。 hCCS 识别和激活 SOD1 的分子机制尚不清楚。为了更好地理解这一生化途径，我们以 2.75 埃的分辨率确定了 hCCS 最大结构域（hCCS 结构域 II）的 X 射线结构。整体结构与其靶酶SOD1密切相关，由八链β-桶和由两个延伸环形成的锌结合位点组成。第一个环为结合的锌离子提供配体，类似于 SOD1 中的锌子环。第二种在结构上类似于 SOD1 静电通道环，但缺乏许多对催化重要的残基。与 SOD1 和 yCCS 一样，hCCS 使用高度保守的界面形成二聚体。然而，与 SOD1 相比，hCCS 结构不包含结合在催化位点的铜离子。值得注意的是，该结构揭示了靠近二聚体界面的单环，这是 CCS 伴侣所独有的。
The human copper chaperone for superoxide dismutase (hCCS) delivers the essential copper ion cofactor to copper,zinc superoxide dismutase (SOD1), a key enzyme in antioxidant defense. Mutations in SOD1 are linked to familial amyotrophic lateral sclerosis (FALS), a fatal neurodegenerative disorder. The molecular mechanisms by which SOD1 is recognized and activated by hCCS are not understood. To better understand this biochemical pathway, we have determined the X-ray structure of the largest domain of hCCS (hCCS Domain II) to 2.75 Angstrom resolution. The overall structure is closely related to that of its target enzyme SOD1, consisting of an eight-stranded beta-barrel and a zinc-binding site formed by two extended loops. The first of these loops provides the ligands to a bound zinc ion, and is analogous to the zinc subloop in SOD1. The second structurally resembles the SOD1 electrostatic channel loop, but lacks many of the residues important for catalysis. Like SOD1 and yCCS, hCCS forms a dimer using a highly conserved interface. In contrast to SOD1, however, the hCCS structure does not contain a copper ion bound in the catalytic site. Notably, the structure reveals a single loop proximal to the dimer interface which is unique to the CCS chaperones.