Cell
Volume 185, Issue 12, 9 June 2022, Pages 2148-2163.e27
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Article
Zn-regulated GTPase metalloprotein activator 1 modulates vertebrate zinc homeostasis

https://doi.org/10.1016/j.cell.2022.04.011Get rights and content
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Highlights

  • The N terminus of ZNG1 interacts with the zinc finger of METAP1

  • ZNG1 promotes METAP1 activity in a GTP-hydrolysis- and Zn-dependent manner

  • Loss of ZNG1 impairs mitochondrial function and cellular proliferation

  • Zng1 mutant animals are sensitive to Zn starvation and inhibition of METAP activity

Summary

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

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

Data and code availability

  • Yeast-two-hybrid data are provided within Table S1. Proteomics data are provided within Tables S3 and S4. Additionally, all mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier ProteomeXchange: PXD031516. NMR structure information is provided within Table S2 and the structure is deposited on PDB:7SEK. All backbone and side chain chemical shifts have been deposited in the BioMagResBank under accession number BMRB: 51117 (free), BMRB: 51118 (bound), and BMRB: 30956 (fusion) (Ulrich et al., 2008). Backbone relaxation rates have been deposited under accession numbers BMRB: 51117 (free) and BMRB: 51119 (fusion). The AlphaFold2 structural model of the yeast complex is available in ModelArchive at https://modelarchive.org/doi/10.5452/ma-1hnkh.

  • Code used in this study is in supplemental methods S1 (Methods S1).

  • Any additional information required to reanalyze the data reported in this paper is available from the Lead Contact upon request.

Cited by (0)

8

These authors contributed equally

9

Lead contact