Evolutionary rate covariation identifies SLC30A9 (ZnT9) as a mitochondrial zinc transporter.
Evolutionary rate covariation identifies SLC30A9 (ZnT9) as a mitochondrial zinc transporter.
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DOI：
10.1042/bcj20210342
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发表时间：
2021-09-17
影响因子：
4.1
通讯作者：
Kiselyov, Kirill
中科院分区：
文献类型：
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作者：
Kowalczyk, Amanda;Gbadamosi, Omotola;Kolor, Kathryn;Sosa, Jahree;Andrzejczuk, Livia;Gibson, Gregory;St Croix, Claudette;Chikina, Maria;Aizenman, Elias;Clark, Nathan;Kiselyov, Kirill
基因组测序的最新进展已经导致新的离子和代谢物转运蛋白的鉴定，其中许多尚未被表征。由于各种亚细胞定位，货物和运输机制，这样的表征是一项艰巨的任务，和预测的方法集中在功能背景下的转运是非常需要的。在这里，我们提出了一种情况下，用于确定转运定位使用进化速率协变（ERC），一种计算方法的基础上成对相关的氨基酸序列的进化速率在整个哺乳动物胚胎发育。作为一个案例研究，我们发现，不佳的特点转运蛋白SLC30A9（ZnT9）与线粒体氧化磷酸化链的几个组成部分的共同进化，这表明线粒体定位。我们使用重组人SLC30A9通过实验证实了这一计算发现。SLC30A9的缺失导致线粒体中锌的错误处理，这表明在正常条件下它作为锌的输出者。因此，我们建议，ERC可以用来预测新的转运蛋白和其他不良特征的蛋白质的功能背景。
Recent advances in genome sequencing have led to the identification of new ion and metabolite transporters, many of which have not been characterized. Due to the variety of subcellular localizations, cargo and transport mechanisms, such characterization is a daunting task, and predictive approaches focused on the functional context of transporters are very much needed. Here we present a case for identifying a transporter localization using evolutionary rate covariation (ERC), a computational approach based on pairwise correlations of amino acid sequence evolutionary rates across the mammalian phylogeny. As a case study, we find that poorly characterized transporter SLC30A9 (ZnT9) coevolves with several components of the mitochondrial oxidative phosphorylation chain, suggesting mitochondrial localization. We confirmed this computational finding experimentally using recombinant human SLC30A9. SLC30A9 loss caused zinc mishandling in the mitochondria, suggesting that under normal conditions it acts as a zinc exporter. We therefore propose that ERC can be used to predict the functional context of novel transporters and other poorly characterized proteins.