Evolutionary rate covariation identifies SLC30A9 (ZnT9) as a mitochondrial zinc transporter

Biochem J. 2021 Sep 17;478(17):3205-3220. doi: 10.1042/BCJ20210342.

Abstract

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.

Keywords: cellular localization; evolutionary biology; molecular evolution; zinc transport.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism*
  • Cation Transport Proteins / genetics*
  • Cation Transport Proteins / metabolism*
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism*
  • Computational Biology / methods*
  • Evolution, Molecular*
  • Gene Knockdown Techniques
  • HeLa Cells
  • Humans
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / metabolism
  • Phylogeny
  • Signal Transduction / genetics*
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*
  • Transfection
  • Whole Genome Sequencing / methods
  • Zinc / metabolism

Substances

  • Carrier Proteins
  • Cation Transport Proteins
  • Cell Cycle Proteins
  • Mitochondrial Proteins
  • SLC30A9 protein, human
  • Transcription Factors
  • zinc-binding protein
  • Zinc