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.
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Cover Image
Cover Image
In blood, angiotensinogen is found in either the oxidised or reduced form, with elevated levels of the oxidised form found in several hypertensive conditions. Molecular dynamics simulations predict that the disulfide bond present in the oxidised form, shown here as glowing orange spheres, constrains the movements of the neighbouring A2 helix and the CD loop, but also leads to increased conformational sampling of the N-terminus. We observe a difference in antibody binding affinity for the N-terminus between the two redox forms of angiotensinogen which is consistent with this prediction and could be used in a diagnostic setting to assess the progression of hypertensive disorders, such as pre-eclampsia. For more, see the article by Crowther and colleagues (pp. 3319–3330). Image created by Biovidera, courtesy of Ashley Buckle and Benjamin Porebski.
Evolutionary rate covariation identifies SLC30A9 (ZnT9) as a mitochondrial zinc transporter
