Department of Pathology, Microbiology, and Immunology, Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
Cell. 2022 Jun 9;185(12):2148-2163.e27. doi: 10.1016/j.cell.2022.04.011. Epub 2022 May 17.
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）是生物体中多达 10%的蛋白质的必需微量元素和辅因子。在 Zn 限制的情况下，预测专门的酶称为金属伴侣蛋白将 Zn 分配给特定的金属蛋白酶。该功能已被假定分配给 G3E GTPase COG0523 蛋白，但在任何生物体中都没有实验鉴定出 Zn 金属伴侣蛋白。在这里，我们对脊椎动物中保守的 COG0523 蛋白家族进行了功能表征。我们确定 Zn 金属蛋白酶蛋氨酸氨肽酶 1（METAP1）为 COG0523 的客户，从而将这组 COG0523 蛋白重新命名为 Zn 调节的 GTPase 金属蛋白酶激活剂（ZNG1）家族。使用生物化学、结构、遗传和药理学方法在进化上差异很大的模型中，包括斑马鱼和小鼠，我们证明了 ZNG1 蛋白在调节细胞内 Zn 稳态中的关键作用。总之，这些数据揭示了 Zn 金属伴侣蛋白家族的存在，并赋予 ZNG1 蛋白在细胞内 Zn 运输中的重要作用。
