Metallochaperones and metalloregulation in bacteria

Abstract

Bacterial transition metal homoeostasis or simply ‘metallostasis’ describes the process by which cells control the intracellular availability of functionally required metal cofactors, from manganese (Mn) to zinc (Zn), avoiding bothmetal deprivation and toxicity. Metallostasis is an emerging aspect of the vertebrate host–pathogen interface that is defined by a ‘tug-of-war’ for biologically essential metals and provides the motivation for much recent work in this area. The host employs a number of strategies to starve the microbial pathogen of essential metals, while for others attempts to limit bacterial infections by leveraging highly competitive metals. Bacteria must be capable of adapting to these efforts to remodel the transition metal landscape and employ highly specialized metal sensing transcriptional regulators, termed metalloregulatory proteins, and metallochaperones, that allocate metals to specific destinations, to mediate this adaptive response. In this essay, we discuss recent progress in our understanding of the structural mechanisms and metal specificity of this adaptive response, focusing on energy-requiring metallochaperones that play roles in the metallocofactor active site assembly in metalloenzymes and metallosensors, which govern the systems-level response to metal limitation and intoxication.

The two-component system CopRS maintains femtomolar levels of free copper in the periplasm ofPseudomonas aeruginosausing a phosphatase-based mechanism

“…It would be quite speculative to compare such dissimilar determinations. However, it might be instructive to consider the observed 10 −19 –10 −21 M affinities of cytoplasmic copper sensors in general (51, 59); and those determined for the cytoplasmic triad CopZ2/CueR/CopZ1 of P. aeruginosa , with relative affinities for Cu + ranging between 10 −15 – 10 −17 M (9, 11). The weaker affinity of CopS compared to the cytoplasmic regulators and chaperones, is likely the consequence of a metal binding site formed by His rather than Cys residues.…”

Activation of a zinc metallochaperone by the alarmone ZTP

“…Metallochaperones play a central role in metal homeostasis by delivering metal cofactors to their cognate proteins, thereby providing metal specificity as well as preventing toxicity associated with free cytosolic metal ions (20). The ZagA zinc metallochaperone belongs to subfamily 1 of the COG0523 family of G3E GTPases, proteins associated with the maturation of metal dependent proteins.…”

“…ZagA is a member of the zinc-associated subfamily 1 of the COG0523 family G3E GTPases (19). COG0523 proteins are evolutionarily related to well characterized nickel metallochaperones, including UreG for urease and HypB for nickel hydrogenase (20). The functions of COG0523 proteins, which are found in all domains of life, are generally associated with the assembly or function of metalloproteins.…”

Rapid, Low-Cost Detection of Water Contaminants Using RegulatedIn VitroTranscription

“…The above results show that aTFs can be used to regulate IVT in response to ligands through derepression of operator binding. However, there are aTFs, often referred to as aporepressors, that function in the inverse manner-by binding the operator site only when bound to their cognate ligands [36][37][38]. While this ligand corepression represents an important control of gene expression, it is not as useful in a diagnostic biosensor context where direct activation of visible outputs upon exposure to target ligands is often desired.…”