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.

锌 (Zn) 是一种必需的微量营养素，也是生物体内高达 10% 蛋白质的辅助因子。在 Zn 限制期间，预计称为金属伴侣的特殊酶会将 Zn 分配给特定的金属蛋白。此功能已被推定分配给 G3E GTPase COG0523 蛋白，但尚未在任何生物体中通过实验鉴定出锌金属伴侣。在这里，我们在功能上描述了一个跨脊椎动物保守的 COG0523 蛋白家族。我们将锌金属蛋白酶甲硫氨酸氨基肽酶 1 (METAP1) 鉴定为 COG0523 客户，导致将这组 COG0523 蛋白重新指定为锌调节的 GTP 酶金属蛋白激活剂 (ZNG1) 家族。使用生化、结构、遗传和药理学方法跨越进化不同的模型，包括斑马鱼和小鼠，我们证明了 ZNG1 蛋白在调节细胞锌稳态中的关键作用。总的来说，这些数据揭示了锌金属伴侣家族的存在，并赋予 ZNG1 在细胞内锌运输中的重要作用。