Molecular and Biochemical Characterization of a Unique Mutation in CCS, the Human Copper Chaperone to Superoxide Dismutase
Molecular and Biochemical Characterization of a Unique Mutation in CCS, the Human Copper Chaperone to Superoxide Dismutase
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DOI：
10.1002/humu.22099
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发表时间：
2012-08-01
期刊：
影响因子：
3.9
通讯作者：
Gaertner, Jutta
中科院分区：
文献类型：
--
作者：
Huppke, Peter;Brendel, Cornelia;Gaertner, Jutta
铜（Cu）是一种微量金属，容易获得和提供电子，这一特性使其作为酶辅因子是理想的，但作为自由基的来源是危险的。为了调节细胞铜代谢，一个精心设计的伴侣和转运蛋白系统已经进化，虽然没有人铜伴侣突变已被描述到目前为止。我们描述了一个孩子从一个近亲家庭谁继承纯合子突变SLC 33 A1，编码乙酰辅酶A转运蛋白，并在CCS，编码铜分子伴侣超氧化物歧化酶。CCS突变，p.Arg163Trp，预测在位置163处高度保守的精氨酸残基被CCS结构域II中的色氨酸取代，其直接与超氧化物歧化酶1（SOD 1）相互作用。患者的成纤维细胞，哺乳动物细胞转染，免疫沉淀试验，和Lys 71（CCS同源）酵母互补的生化分析支持突变的致病性。CCS的表达减少，CCS与SOD 1的结合受损。因此，这种突变导致SOD 1活性降低，并可能损害其他机制的重要正常铜稳态。CCS-Arg 163 Trp代表编码Cu分子伴侣的基因中的人类突变的主要实例。《明史》卷33：1207-1215。(c)2012 Wiley Periodicals，Inc.
Copper (Cu) is a trace metal that readily gains and donates electrons, a property that renders it desirable as an enzyme cofactor but dangerous as a source of free radicals. To regulate cellular Cu metabolism, an elaborate system of chaperones and transporters has evolved, although no human Cu chaperone mutations have been described to date. We describe a child from a consanguineous family who inherited homozygous mutations in the SLC33A1, encoding an acetyl CoA transporter, and in CCS, encoding the Cu chaperone for superoxide dismutase. The CCS mutation, p.Arg163Trp, predicts substitution of a highly conserved arginine residue at position 163, with tryptophan in domain II of CCS, which interacts directly with superoxide dismutase 1 (SOD1). Biochemical analyses of the patient's fibroblasts, mammalian cell transfections, immunoprecipitation assays, and Lys71 (CCS homolog) yeast complementation support the pathogenicity of the mutation. Expression of CCS was reduced and binding of CCS to SOD1 impaired. As a result, this mutation causes reduced SOD1 activity and may impair other mechanisms important for normal Cu homeostasis. CCS-Arg163Trp represents the primary example of a human mutation in a gene coding for a Cu chaperone. Hum Mutat 33:1207-1215. (c) 2012 Wiley Periodicals, Inc.