Department of Physiology, Johns Hopkins University, Baltimore, MD, USA.
Metallomics. 2019 Jun 19;11(6):1128-1139. doi: 10.1039/c9mt00057g.
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 properties in vitro and influence serum copper (Cu) status in 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.
单核苷酸多态性（SNPs）是人类基因组中序列变异的最大来源。然而，它们的功能意义尚不清楚。我们表明，导致氨基酸替换 K832R 和 R952K 的 Wilson 病基因 ATP7B 中的 SNPs，在体外调节 ATP7B 的性质，并影响体内血清铜（Cu）状态。存在 R832 与 ATP7B 丰度降低以及响应升高的 Cu 而减少的运输有关。K832R 取代改变了执行器结构域中氨基酸残基的表面暴露，并增加了其构象灵活性。所有与 SNP 相关的 ATP7B 变体（R832/R952、R832/K952、K832/K952 和 K832/R952）都具有 Cu 转运活性。然而，与其他变体相比，ATP7B-K832/K952 的活性较低。在人类中，存在 K952 与血清中可交换的 Cu 分数较高有关。因此，SNP 可能调节 ATP7B 的性质和生物体的 Cu 状态。
