The structural and functional analysis of copper transporting P-type ATPase in inborn error of copper metabolism

1.门克斯病基因（ATP-7A）蛋白和威尔逊病基因（ATP-7 B）蛋白的细胞内定位在稳定条件下，ATP-7A和ATP-7 B合成的蛋白均定位于trans-Golgi网络中。细胞内铜浓度的增加导致这些蛋白质快速移动到细胞质囊泡区室。ATP-7A和7 B蛋白的这种铜特异性细胞再分布是一个可逆的过程，不依赖于新的蛋白（铜转运小泡）的出现。2. Wilson病基因型与临床特征的相关性肝型（包括暴发型）Wilson病ATP-7 B突变多为一点稀释突变，使读码框移位。截短的蛋白质必须从这些突变的基因合成。这些蛋白质可能没有任何铜转运蛋白的功能。有神经系统症状的患者存在错义突变和外显子跳跃。这些突变的蛋白质可以保留部分功能。这些结果表明，肝豆状核变性的表型差异取决于肝豆状核变性蛋白的功能水平。蛋白质功能受基因突变类型（基因型）的调节。ATP-7 B的严重损伤，如一个碱基的缺失将导致功能丧失，导致严重的肝功能障碍，如暴发型肝豆状核变性。

1.The intracellular localization of Menkes disease gene (ATP-7A) protein and Wilson disease gene (ATP-7B) proteinBoth of the proteins synthesized from ATP-7A and 7B were localized in the trans-Golgi network under steady conditions. An increase in the intracellular copper concentration resulted in the rapid movement of these proteins to a cytoplasmic vesicular compartment. This copper-specific cellular redistribution of ATP-7A and 7B protein is a reversible process that occurs independent of new protein (small vesicles of copper transport).2.The corelationship between genotype and clinical features in Wilson diseaseThe most of mutations of ATP-7B in hepatic type (including fulminant type) of Wilson disease were one point dilutions that make frame shift. Truncated proteins must be synthesized from these mutated genes. And these proteins may have no any function as a Copper transporter. The patients who have neurologic symptom revealed missense mutation and exon skipping. These mutated protein can be leave some part of function. These results suggest that difference of phenotypes of Wilson disease depend on functional levels of Wilson disease protein. And protein function is regulated by types of gene mutations (genotype). The sever impairment of ATP-7B,such one base deletion would remove function, leads to sever liver dysfunction, such as fulminant type of Wilson disease.