Transition metal homeostasis ensures that cells and organisms obtain sufficient metal to meet cellular demand while dispensing with any excess so as to avoid toxicity. In bacteria, zinc restriction induces the expression of one or more Zur (zinc-uptake repressor)-regulated Cluster of Orthologous Groups (COG) COG0523 proteins. COG0523 proteins encompass a poorly understood sub-family of G3E P-loop small GTPases, others of which are known to function as metallochaperones in the maturation of cobalamin (CoII) and NiII cofactor-containing metalloenzymes. Here, we use genomic enzymology tools to functionally analyse over 80 000 sequences that are evolutionarily related to Acinetobacter baumannii ZigA (Zur-inducible GTPase), a COG0523 protein and candidate zinc metallochaperone. These sequences segregate into distinct sequence similarity network (SSN) clusters, exemplified by the ZnII-Zur-regulated and FeIII-nitrile hydratase activator CxCC (C, Cys; X, any amino acid)-containing COG0523 proteins (SSN cluster 1), NiII-UreG (clusters 2, 8), CoII-CobW (cluster 4), and NiII-HypB (cluster 5). A total of five large clusters that comprise ≈ 25% of all sequences, including cluster 3 which harbors the only structurally characterized COG0523 protein, Escherichia coli YjiA, and many uncharacterized eukaryotic COG0523 proteins. We also establish that mycobacterial-specific protein Y (Mpy) recruitment factor (Mrf), which promotes ribosome hibernation in actinomycetes under conditions of ZnII starvation, segregates into a fifth SSN cluster (cluster 17). Mrf is a COG0523 paralog that lacks all GTP-binding determinants as well as the ZnII-coordinating Cys found in CxCC-containing COG0523 proteins. On the basis of this analysis, we discuss new perspectives on the COG0523 proteins as cellular reporters of widespread nutrient stress induced by ZnII limitation.

中文翻译：

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COG0523 蛋白：一个功能多样的过渡金属调节 G3E P 环 GTP 水解酶家族，从细菌到人类。

过渡金属稳态可确保细胞和生物体获得足够的金属以满足细胞需求，同时避免任何过量金属以避免毒性。在细菌中，锌限制会诱导一种或多种 Zur（锌摄取抑制因子）调节的直系同源群 (COG) COG0523 蛋白的表达。COG0523 蛋白包含一个鲜为人知的 G3E P 环小 GTP 酶亚家族，已知其他亚家族在钴胺素 (CoII) 和含 NiII 辅因子的金属酶的成熟过程中起金属伴侣的作用。在这里，我们使用基因组酶学工具对 80 000 多个序列进行功能分析，这些序列在进化上与鲍曼不动杆菌 ZigA（Zur 诱导型 GTP 酶）、COG0523 蛋白和候选锌金属伴侣蛋白相关。这些序列分离成不同的序列相似性网络 (SSN) 簇，例如 ZnII-Zur 调节和 FeIII-腈水合酶激活剂 CxCC（C，Cys；X，任何氨基酸）含有 COG0523 蛋白（SSN 簇 1），NiII -UreG（簇 2、8）、CoII-CobW（簇 4）和 NiII-HypB（簇 5）。总共包含 ≈ 25% 的所有序列的五个大簇，包括簇 3，它包含唯一具有结构特征的 COG0523 蛋白、大肠杆菌 YjiA 和许多未表征的真核 COG0523 蛋白。我们还确定分枝杆菌特异性蛋白 Y (Mpy) 募集因子 (Mrf) 在 ZnII 饥饿条件下促进放线菌核糖体休眠，分离到第五个 SSN 簇（簇 17）中。Mrf 是一个 COG0523 旁系同源物，它缺乏所有 GTP 结合决定簇以及在含有 CxCC 的 COG0523 蛋白中发现的 ZnII 配位半胱氨酸。在此分析的基础上，我们讨论了 COG0523 蛋白作为 ZnII 限制诱导的广泛营养胁迫的细胞报告者的新观点。