Mammalian copper chaperone Cox17p has an essential role in activation of cytochrome c oxidase and embryonic development
Mammalian copper chaperone Cox17p has an essential role in activation of cytochrome c oxidase and embryonic development
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DOI：
10.1128/mcb.22.21.7614-7621.2002
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发表时间：
2002-11-01
影响因子：
5.3
通讯作者：
Munekata, E
中科院分区：
文献类型：
--
作者：
Takahashi, Y;Kako, K;Munekata, E
Cox 17 p对于功能性细胞色素c氧化酶（CCO）的组装和将铜离子递送到插入酵母中的酶的载体是必需的。虽然这种小蛋白已经从人类、小鼠和猪中克隆或纯化，但Cox 17 p在哺乳动物系统中的功能尚未阐明。哺乳动物Cox 17 p的体外生物化学数据表明，铜与序列-KPCCAC-结合。虽然COX 17破坏的小鼠胚胎纯合子在胚胎日E8.5和E10之间死亡，但它们正常发育，直到E6.5。这种表型与细胞表面铜转运蛋白Ctr 1（-/-）的胚胎在原肠胚形成前后的致死性方面惊人地相似。COX 17缺陷胚胎在E6.5时表现出CCO活性的严重降低。琥珀酸脱氢酶活性和抗COX亚基抗体的免疫反应性在COX 17（-/-）胚胎中是正常的，表明这种缺陷不是由其他复合物和/或亚基的缺乏引起的，而是由Cox 17 p受损的CCO激活引起的。由于其他铜分子伴侣（Atox 1和CCS）缺陷小鼠表现出更中度的缺陷，COX 17基因座的破坏导致仅表达Ctr 1（-/-）表型。我们发现，乳酸脱氢酶的活性在E6.5胚胎也是正常的，这意味着CCO的激活Cox 17 p可能不是必需的原肠胚形成前的胚胎发生的进展。
Cox17p is essential for the assembly of functional cytochrome c oxidase (CCO) and for delivery of copper ions to the mitochondrion for insertion into the enzyme in yeast. Although this small protein has already been cloned or purified from humans, mice, and pigs, the function of Cox17p in the mammalian system has not yet been elucidated. In vitro biochemical data for mammalian Cox17p indicate that the copper binds to the sequence -KPCCAC-. Although mouse embryos homozygous for COX17 disruption die between embryonic days E8.5 and E10, they develop normally until E6.5. This phenotype is strikingly similar to embryos of Ctr1(-/-), a cell surface copper transporter, in its lethality around the time of gastrulation. COX17-deficient embryos exhibit severe reductions in CCO activity at E6.5. Succinate dehydrogenase activity and immunoreactivities for anti-COX subunit antibodies were normal in the COX17(-/-) embryos, indicating that this defect was not caused by the deficiency of other complexes and/or subunits but was caused by impaired CCO activation by Cox17p. Since other copper chaperone (Atox1 and CCS)-deficient mice show a more moderate defect, the disruption of the COX17 locus causes the expression of only the phenotype of Ctr1(-/-). We found that the activity of lactate dehydrogenase was also normal in E6.5 embryos, implying that the activation of CCO by Cox17p may not be essential to the progress of embryogenesis before gastrulation.