Single nucleotide polymorphisms in the human ATP7B gene modify the properties of the ATP7B protein.
Single nucleotide polymorphisms in the human ATP7B gene modify the properties of the ATP7B protein.
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人类 ATP7B 基因中的单核苷酸多态性改变了 ATP7B 蛋白的特性。
DOI：
10.1039/c9mt00057g
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Lutsenko,Svetlana
中科院分区：
文献类型：
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作者：
McCann,CourtneyJ;Jayakanthan,Samuel;Siotto,Mariacristina;Yang,Nan;Osipova,Maria;Squitti,Rosanna;Lutsenko,Svetlana
单核苷酸多态(SNPs)是人类基因组序列变异的最大来源。然而，它们的功能意义还没有被很好地理解。我们发现，肝豆状核变性基因ATP7B中的SNPs产生K832R和R952K氨基酸替换，在体外调节ATP7B的特性，并在体内影响血清铜(Cu)状态。R832的存在与ATP7B丰度降低和对铜升高的反应减少有关。K832R取代改变了致动器结构域中氨基酸残基的表面暴露，增加了其构象灵活性。所有与SNP相关的ATP7B变异体(R832/R952、R832/K952、K832/K952和K832/R952)都具有铜转运活性。然而，ATP7B-K832/K952的活性低于其他变异体。在人类中，K952的存在与血清中更高比例的可交换铜有关。因此，SNPs可能调节ATP7B的性质和生物体的铜状态。
Single nucleotide polymorphisms (SNPs) are the largest source of sequence variation in the human genome. However, their functional significance is not well understood. We show that SNPs in the Wilson disease gene,ATP7B, that produce amino-acid substitutions K832R and R952K, modulate ATP7B propertiesin vitroand influence serum copper (Cu) statusin vivo. The presence of R832 is associated with a lower ATP7B abundance and a diminished trafficking in response to elevated Cu. The K832R substitution alters surface exposure of amino acid residues in the actuator domain and increases its conformational flexibility. All SNP-related ATP7B variants (R832/R952, R832/K952, K832/K952, and K832/R952) have Cu-transport activity. However, the activity of ATP7B-K832/K952 is lower compared to other variants. In humans, the presence of K952 is associated with a higher fraction of exchangeable Cu in serum. Thus, SNPs may modulate the properties of ATP7B and the organism Cu status.