Zn-regulated GTPase Metalloprotein Activator 1 Modulates Vertebrate Zinc Homeostasis

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2022 May 18

PMID 35584702

Authors

Andy Weiss

Caitlin C Murdoch

Katherine A Edmonds

Matthew R Jordan

Andrew J Monteith

Yasiru R Perera

Aslin M Rodriguez Nassif

Amber M Petoletti

William N Beavers

Matthew J Munneke

Sydney L Drury

Evan S Krystofiak

Kishore Thalluri

Hongwei Wu

Angela R S Kruse

Richard D DiMarchi

Richard M Caprioli

Jeffrey M Spraggins

Walter J Chazin

David P Giedroc

Eric P Skaar

Affiliations

Soon will be listed here.

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.

Citing Articles

Decoding the Implications of Zinc in the Development and Therapy of Leukemia.

Zhu B, Yang C, Hua S, Li K, Shang P, Li Z Adv Sci (Weinh). 2025; 12(9):e2412225.

PMID: 39887881 PMC: 11884550. DOI: 10.1002/advs.202412225.

The interplay between ZigA and SltB promotes zinc homeostasis and cell envelope integrity.

Critchlow J, Barraza J, Munneke M, Krystofiak E, Green E, Skaar E Infect Immun. 2025; 93(2):e0042224.

PMID: 39846731 PMC: 11834433. DOI: 10.1128/iai.00422-24.

A metal-trap tests and refines blueprints to engineer cellular protein metalation with different elements.

Clough S, Young T, Tarrant E, Scott A, Chivers P, Glasfeld A Nat Commun. 2025; 16(1):810.

PMID: 39827241 PMC: 11742986. DOI: 10.1038/s41467-025-56199-w.

Activity of the mammalian DNA transposon piggyBat from Myotis lucifugus is restricted by its own transposon ends.

Hickman A, Lannes L, Furman C, Hong C, Franklin L, Ghirlando R Nat Commun. 2025; 16(1):458.

PMID: 39774116 PMC: 11707139. DOI: 10.1038/s41467-024-55784-9.

Unlocking the brain's zinc code: implications for cognitive function and disease.

Sabouri S, Rostamirad M, Dempski R Front Biophys. 2025; 2.

PMID: 39758530 PMC: 11698502. DOI: 10.3389/frbis.2024.1406868.

References

Gamerdinger M, Kobayashi K, Wallisch A, Kreft S, Sailer C, Schlomer R . Early Scanning of Nascent Polypeptides inside the Ribosomal Tunnel by NAC. Mol Cell. 2019; 75(5):996-1006.e8. DOI: 10.1016/j.molcel.2019.06.030. View

Kateb F, Perrin H, Tripsianes K, Zou P, Spadaccini R, Bottomley M . Structural and functional analysis of the DEAF-1 and BS69 MYND domains. PLoS One. 2013; 8(1):e54715. PMC: 3555993. DOI: 10.1371/journal.pone.0054715. View

Huet D, Rajendran E, van Dooren G, Lourido S . Identification of cryptic subunits from an apicomplexan ATP synthase. Elife. 2018; 7. PMC: 6133553. DOI: 10.7554/eLife.38097. View

MacLean B, Tomazela D, Shulman N, Chambers M, Finney G, Frewen B . Skyline: an open source document editor for creating and analyzing targeted proteomics experiments. Bioinformatics. 2010; 26(7):966-8. PMC: 2844992. DOI: 10.1093/bioinformatics/btq054. View

Zhang Y, Griffith E, Sage J, Jacks T, Liu J . Cell cycle inhibition by the anti-angiogenic agent TNP-470 is mediated by p53 and p21WAF1/CIP1. Proc Natl Acad Sci U S A. 2000; 97(12):6427-32. PMC: 18619. DOI: 10.1073/pnas.97.12.6427. View

Robert X, Gouet P . Deciphering key features in protein structures with the new ENDscript server. Nucleic Acids Res. 2014; 42(Web Server issue):W320-4. PMC: 4086106. DOI: 10.1093/nar/gku316. View

Mortensen B, Rathi S, Chazin W, Skaar E . Acinetobacter baumannii response to host-mediated zinc limitation requires the transcriptional regulator Zur. J Bacteriol. 2014; 196(14):2616-26. PMC: 4097591. DOI: 10.1128/JB.01650-14. View

Forman H, Kennedy J . Role of superoxide radical in mitochondrial dehydrogenase reactions. Biochem Biophys Res Commun. 1974; 60(3):1044-50. DOI: 10.1016/0006-291x(74)90418-5. View

Rosenzweig A . Metallochaperones: bind and deliver. Chem Biol. 2002; 9(6):673-7. DOI: 10.1016/s1074-5521(02)00156-4. View

10.

Jonckheere V, Fijalkowska D, Van Damme P . Omics Assisted N-terminal Proteoform and Protein Expression Profiling On Methionine Aminopeptidase 1 (MetAP1) Deletion. Mol Cell Proteomics. 2018; 17(4):694-708. PMC: 5880116. DOI: 10.1074/mcp.RA117.000360. View

11.

HaileMariam M, Eguez R, Singh H, Bekele S, Ameni G, Pieper R . S-Trap, an Ultrafast Sample-Preparation Approach for Shotgun Proteomics. J Proteome Res. 2018; 17(9):2917-2924. DOI: 10.1021/acs.jproteome.8b00505. View

12.

Stetefeld J, McKenna S, Patel T . Dynamic light scattering: a practical guide and applications in biomedical sciences. Biophys Rev. 2017; 8(4):409-427. PMC: 5425802. DOI: 10.1007/s12551-016-0218-6. View

13.

Uhlen M, Fagerberg L, Hallstrom B, Lindskog C, Oksvold P, Mardinoglu A . Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419. DOI: 10.1126/science.1260419. View

14.

Li X, Chang Y . Amino-terminal protein processing in Saccharomyces cerevisiae is an essential function that requires two distinct methionine aminopeptidases. Proc Natl Acad Sci U S A. 1995; 92(26):12357-61. PMC: 40356. DOI: 10.1073/pnas.92.26.12357. View

15.

Gibbs D, Bacardit J, Bachmair A, Holdsworth M . The eukaryotic N-end rule pathway: conserved mechanisms and diverse functions. Trends Cell Biol. 2014; 24(10):603-11. DOI: 10.1016/j.tcb.2014.05.001. View

16.

Lee W, Tonelli M, Markley J . NMRFAM-SPARKY: enhanced software for biomolecular NMR spectroscopy. Bioinformatics. 2014; 31(8):1325-7. PMC: 4393527. DOI: 10.1093/bioinformatics/btu830. View

17.

ARFIN S, Bradshaw R . Cotranslational processing and protein turnover in eukaryotic cells. Biochemistry. 1988; 27(21):7979-84. DOI: 10.1021/bi00421a001. View

18.

Hilty C, Wider G, Fernandez C, Wuthrich K . Stereospecific assignments of the isopropyl methyl groups of the membrane protein OmpX in DHPC micelles. J Biomol NMR. 2003; 27(4):377-82. DOI: 10.1023/a:1025877326533. View

19.

Guilbert J . The world health report 2002 - reducing risks, promoting healthy life. Educ Health (Abingdon). 2004; 16(2):230. DOI: 10.1080/1357628031000116808. View

20.

Ulrich E, Akutsu H, Doreleijers J, Harano Y, Ioannidis Y, Lin J . BioMagResBank. Nucleic Acids Res. 2007; 36(Database issue):D402-8. PMC: 2238925. DOI: 10.1093/nar/gkm957. View