1. Academic Validation
  2. Zn-regulated GTPase metalloprotein activator 1 modulates vertebrate zinc homeostasis

Zn-regulated GTPase metalloprotein activator 1 modulates vertebrate zinc homeostasis

  • Cell. 2022 Jun 9;185(12):2148-2163.e27. doi: 10.1016/j.cell.2022.04.011.
Andy Weiss 1 Caitlin C Murdoch 1 Katherine A Edmonds 2 Matthew R Jordan 3 Andrew J Monteith 1 Yasiru R Perera 4 Aslin M Rodríguez Nassif 4 Amber M Petoletti 1 William N Beavers 1 Matthew J Munneke 1 Sydney L Drury 1 Evan S Krystofiak 5 Kishore Thalluri 2 Hongwei Wu 2 Angela R S Kruse 6 Richard D DiMarchi 2 Richard M Caprioli 6 Jeffrey M Spraggins 7 Walter J Chazin 4 David P Giedroc 8 Eric P Skaar 9
Affiliations

Affiliations

  • 1 Department of Pathology, Microbiology, and Immunology, Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • 2 Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
  • 3 Department of Chemistry, Indiana University, Bloomington, IN 47405, USA; Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN 47405, USA.
  • 4 Departments of Biochemistry and Chemistry, Center for Structural Biology, Vanderbilt University, Nashville, TN 37240, USA.
  • 5 Cell Imaging Shared Resource, Vanderbilt University, Nashville, TN 37232, USA.
  • 6 Departments of Chemistry and Biochemistry, Mass Spectrometry Research Center, Vanderbilt University, Nashville, TN 37235, USA.
  • 7 Departments of Chemistry and Biochemistry, Mass Spectrometry Research Center, Vanderbilt University, Nashville, TN 37235, USA; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA.
  • 8 Department of Chemistry, Indiana University, Bloomington, IN 47405, USA; Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN 47405, USA. Electronic address: [email protected].
  • 9 Department of Pathology, Microbiology, and Immunology, Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: [email protected].
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.

Keywords

CBWD; COG0523; GTPase; METAP1; ZNG1; metallochaperone; metalloprotein; zf-C6H2; zinc; zinc finger.

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