GTP hydrolysis-powered zinc metallochaperones as molecular switches.

Late d-block first row transition metals from manganese to copper and zinc are present in all cells at high abundance and typically cofactor approximately one-third of the proteome. The integrity of this metalloproteome must be functionally resilient to changes in metal bioavailability induced by metal toxicity and metal scarcity, such that cellular processes dependent on these metalloenzymes are maintained. An emerging hypothesis is that the cellular response to zinc scarcity involves the expression of one or more GTP hydrolysis-dependent zinc metallochaperones, which are proposed to allocate zinc to specific downstream "clients". Here we critically evaluate the available evidence in support of this hypothesis with a focus on Cluster of Orthologous Groups 0523 (COG0523) superfamily of nucleotide-dependent metallochaperones. These enzymes are found in all kingdoms and yet the identification of biochemically validated client proteins continues to lag. Approaches to close this knowledge gap are discussed.