Department of Biochemistry and Molecular Biology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Ramat Aviv 69978, Israel.
Metallomics. 2012 Jul;4(7):669-78. doi: 10.1039/c2mt20025b. Epub 2012 Jun 13.
The copper-transporting ATPase ATP7B has an essential role in human physiology, particularly for the liver and brain function. Inactivation of ATP7B is associated with a severe hepato-neurologic disorder, Wilson disease (WD). Hundreds of WD related mutations have been identified in ATP7B to date. The low frequency and the compound-heterozygous nature of causative mutations complicate the analysis of individual mutants and the establishment of genotype-phenotype correlations. To facilitate studies of disease-causing mutations and mechanistic understanding of WD, we have homology-modelled the ATP7B core (residues 643-1377) using the recent structure of the bacterial copper-ATPase LCopA as a template. The model, supported by evolutionary conservation and hydrophobicity analysis, as well as existing and new mutagenesis data, allows molecular interpretations of experimentally characterized clinical mutations. We also illustrate that structure and conservation can be used to grade potential deleterious effects for many WD mutations, which were clinically detected but have not yet been experimentally characterized. Finally, we compare the structural features of ATP7B and LCopA and discuss specific features of the eukaryotic copper pump.
铜转运 ATP 酶 ATP7B 在人体生理学中起着至关重要的作用，特别是对肝脏和大脑功能。ATP7B 的失活与一种严重的肝神经疾病——威尔逊病（WD）有关。迄今为止，已经在 ATP7B 中发现了数百种与 WD 相关的突变。致病突变的低频和复合杂合性质使个体突变体的分析和基因型-表型相关性的建立变得复杂。为了促进对致病突变的研究和对 WD 发病机制的理解，我们使用最近的细菌铜-ATP 酶 LCopA 的结构作为模板，对 ATP7B 核心（残基 643-1377）进行了同源建模。该模型得到了进化保守性和疏水性分析以及现有和新的诱变数据的支持，允许对经过实验表征的临床突变进行分子解释。我们还表明，可以使用结构和保守性来评估许多 WD 突变的潜在有害影响，这些突变已经在临床上检测到，但尚未经过实验表征。最后，我们比较了 ATP7B 和 LCopA 的结构特征，并讨论了真核铜泵的特定特征。
