PUBLICATION

Zn-regulated GTPase metalloprotein activator 1 modulates vertebrate zinc homeostasis

Authors
Weiss, A., Murdoch, C.C., Edmonds, K.A., Jordan, M.R., Monteith, A.J., Perera, Y.R., Rodríguez Nassif, A.M., Petoletti, A.M., Beavers, W.N., Munneke, M.J., Drury, S.L., Krystofiak, E.S., Thalluri, K., Wu, H., Kruse, A.R.S., DiMarchi, R.D., Caprioli, R.M., Spraggins, J.M., Chazin, W.J., Giedroc, D.P., Skaar, E.P.
ID
ZDB-PUB-220519-12
Date
2022
Source
Cell   185(12): 2148-2163.e27 (Journal)
Registered Authors
Murdoch, Caitlin, Skaar, Eric
Keywords
CBWD, COG0523, GTPase, METAP1, ZNG1, metallochaperone, metalloprotein, zf-C6H2, zinc, zinc finger
MeSH Terms
  • Animals
  • Zebrafish/metabolism
  • GTP Phosphohydrolases/metabolism
  • Metallochaperones/metabolism
  • Zinc*/metabolism
  • Mice
  • Metalloendopeptidases/metabolism*
  • Metalloproteins/genetics
  • Homeostasis
(all 9)
PubMed
35584702 Full text @ Cell
Abstract
Zinc (Zn) is an essential micronutrient and cofactor for up to 10% of proteins in living organisms. During Zn limitation, specialized enzymes called metallochaperones are predicted to allocate Zn to specific metalloproteins. This function has been putatively assigned to G3E GTPase COG0523 proteins, yet no Zn metallochaperone has been experimentally identified in any organism. Here, we functionally characterize a family of COG0523 proteins that is conserved across vertebrates. We identify Zn metalloprotease methionine aminopeptidase 1 (METAP1) as a COG0523 client, leading to the redesignation of this group of COG0523 proteins as the Zn-regulated GTPase metalloprotein activator (ZNG1) family. Using biochemical, structural, genetic, and pharmacological approaches across evolutionarily divergent models, including zebrafish and mice, we demonstrate a critical role for ZNG1 proteins in regulating cellular Zn homeostasis. Collectively, these data reveal the existence of a family of Zn metallochaperones and assign ZNG1 an important role for intracellular Zn trafficking.
Genes / Markers
Figures
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
WTcontrolDay 6
WTcontrolDay 6
WTchemical treatment by environment: N-acyl-amino acid, chemical treatment by environment: N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamineDay 4
WTchemical treatment by environment: N-acyl-amino acid, chemical treatment by environment: N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamineDay 4
WTchemical treatment by environment: N-acyl-amino acid, chemical treatment by environment: N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamineDay 5
WTchemical treatment by environment: N-acyl-amino acid, chemical treatment by environment: N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamineDay 5
WTchemical treatment by environment: N-acyl-amino acid, chemical treatment by environment: N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamineDay 6
WTchemical treatment by environment: N-acyl-amino acid, chemical treatment by environment: N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamineDay 6
WTchemical treatment by environment: N-acyl-amino acid, chemical treatment by environment: N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamineDay 6
WTchemical treatment by environment: N-acyl-amino acid, chemical treatment by environment: N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamineDay 6
1 - 10 of 149
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
vu1
    Small Deletion
    vu2
      Small Deletion
      vu3
        Indel
        1 - 3 of 3
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        Human Disease / Model
        No data available
        Sequence Targeting Reagents
        Target Reagent Reagent Type
        cbwdCRISPR1-cbwdCRISPR
        metap1CRISPR1-metap1CRISPR
        1 - 2 of 2
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        Fish
        Antibodies
        No data available
        Orthology
        No data available
        Engineered Foreign Genes
        No data available
        Mapping