Zn-regulated GTPase metalloprotein activator 1 modulates vertebrate zinc homeostasis

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,...

Full description

Saved in:

Bibliographic Details
Published in:	Cell Vol. 185; no. 12; pp. 2148 - 2163.e27
Main Authors:	Weiss, Andy, Murdoch, Caitlin C., Edmonds, Katherine A., Jordan, Matthew R., Monteith, Andrew J., Perera, Yasiru R., Rodríguez Nassif, Aslin M., Petoletti, Amber M., Beavers, William N., Munneke, Matthew J., Drury, Sydney L., Krystofiak, Evan S., Thalluri, Kishore, Wu, Hongwei, Kruse, Angela R.S., DiMarchi, Richard D., Caprioli, Richard M., Spraggins, Jeffrey M., Chazin, Walter J., Giedroc, David P., Skaar, Eric P.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 09-06-2022
Subjects:	Animals CBWD COG0523 GTP Phosphohydrolases - metabolism GTPase Homeostasis metallochaperone Metallochaperones - metabolism Metalloendopeptidases - metabolism metalloprotein Metalloproteins - genetics METAP1 Mice Zebrafish - metabolism zf-C6H2 zinc Zinc - metabolism zinc finger ZNG1 metalloprotein zf-C6H2 CBWD ZNG1 zinc finger metallochaperone zinc GTPase COG0523 METAP1
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
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. [Display omitted] •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 ZNG1 is a putative Zn metallochaperone that supports the activity of Zn-dependent proteins in vertebrates, thereby maintaining Zn homeostasis and cellular integrity.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author Contributions Conceptualization, A.W., C.C.M., K.A.E., M.R.J., D.P.G., E.P.S.; Investigation, A.W., C.C.M., K.A.E., M.R.J., A.J.M., Y.R.P., A.M.R.N., A.M.P., W.N.B., S.L.D., M.J.M., E.S.K., A.R.S.K., H.W.; Formal analysis, A.W., C.C.M., K.A.E., M.R.J. E.S.K.; Resources, K.T., R.D.D; Supervision, R.D.D., J.M.S., R.M.C., W.J.C., D.P.G., E.P.S.; Writing – original draft, A.W., C.C.M., K.A.E., M.R.J., A.J.M., W.J.C., D.P.G., E.P.S.; writing – review & editing, all authors
ISSN:	0092-8674 1097-4172 1097-4172
DOI:	10.1016/j.cell.2022.04.011