Evolutionary rate covariation identifies SLC30A9 (ZnT9) as a mitochondrial zinc transporter.
Amino Acid Sequence
Animals
Carrier Proteins
/ genetics
Cation Transport Proteins
/ genetics
Cell Cycle Proteins
/ genetics
Computational Biology
/ methods
Evolution, Molecular
Gene Knockdown Techniques
HeLa Cells
Humans
Mitochondria
/ metabolism
Mitochondrial Proteins
/ metabolism
Phylogeny
Signal Transduction
/ genetics
Transcription Factors
/ genetics
Transfection
Whole Genome Sequencing
/ methods
Zinc
/ metabolism
cellular localization
evolutionary biology
molecular evolution
zinc transport
Journal
The Biochemical journal
ISSN: 1470-8728
Titre abrégé: Biochem J
Pays: England
ID NLM: 2984726R
Informations de publication
Date de publication:
17 09 2021
17 09 2021
Historique:
received:
12
05
2021
revised:
12
08
2021
accepted:
16
08
2021
pubmed:
17
8
2021
medline:
15
12
2021
entrez:
16
8
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34397090
pii: 229560
doi: 10.1042/BCJ20210342
pmc: PMC10491466
mid: NIHMS1751066
doi:
Substances chimiques
Carrier Proteins
0
Cation Transport Proteins
0
Cell Cycle Proteins
0
Mitochondrial Proteins
0
SLC30A9 protein, human
0
Transcription Factors
0
zinc-binding protein
0
Zinc
J41CSQ7QDS
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3205-3220Subventions
Organisme : NHGRI NIH HHS
ID : R01 HG009299
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS111944
Pays : United States
Informations de copyright
© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.
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