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.

中文翻译：

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进化速率协变将 SLC30A9 (ZnT9) 鉴定为线粒体锌转运蛋白

基因组测序的最新进展导致了新的离子和代谢物转运蛋白的鉴定，其中许多尚未被表征。由于亚细胞定位、货物和运输机制的多样性，这种表征是一项艰巨的任务，非常需要专注于转运蛋白功能背景的预测方法。在这里，我们提出了一个使用进化速率协变 (ERC) 来识别转运蛋白定位的案例，这是一种基于跨哺乳动物系统发育的氨基酸序列进化速率的成对相关性的计算方法。作为案例研究，我们发现特征不佳的转运蛋白 SLC30A9 (ZnT9) 与线粒体氧化磷酸化链的几个成分共同进化，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结果。SLC30A9 丢失导致线粒体中的锌处理不当，这表明在正常条件下它充当锌输出者。因此，我们建议 ERC 可用于预测新型转运蛋白和其他特征不佳的蛋白质的功能背景。