Bacterial Strategies to Maintain Zinc Metallostasis at the Host-Pathogen Interface

Capdevila, Daiana A.; Wang, Jiefei; Giedroc, David P.

doi:10.1074/jbc.r116.742023

Cited by 140 publications

(145 citation statements)

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“…However, metallation of a small subset of Zn II metalloenzymes might require such a metallochaperone, but only under conditions of extreme host-mediated Zn II limitation [23], in the same way that the requirement for the Cu chaperone CCS for Cu, Zn-SOD can be largely bypassed by excess Cu [73]. No zinc chaperone has thus far been unambiguously functionally identified and characterized.…”

Section: Metallochaperonesmentioning

confidence: 99%

“…Our interest in bacterial transition metal homoeostasis is strongly motivated by the impact of this process at the host–pathogen interface and how it is exploited by limiting bacterial infections. This will not, however, be discussed further here and we direct the reader instead to a number of recent reviews on this subject [17,21–23]. We provide sufficient mechanistic detail to pique the interest of the reader, while drawing general conclusions from recent findings in this rapidly expanding field [3,20,90,101].…”

Section: Introductionmentioning

confidence: 99%

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Metallochaperones and metalloregulation in bacteria

Capdevila

Edmonds

Giedroc

2017

Essays in Biochemistry

100

117

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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.

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Section: Metallochaperonesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Metallochaperones and metalloregulation in bacteria

Capdevila

Edmonds

Giedroc

2017

Essays in Biochemistry

100

117

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“…During infection, the host can attack pathogens with high concentrations of Cu and the microbe may, in turn, use this host Cu to charge its extracellular SODs to defend against O 2 ·− produced by the host 113–115, 129 . Since Cu-only SODs have no requirement for Zn, their activity is not impacted by Zn bioavailability, which can vary greatly within the host during infection 102, 130–132 .…”

Section: Fungal Pathogensmentioning

confidence: 99%

Chemical Warfare at the Microorganismal Level: A Closer Look at the Superoxide Dismutase Enzymes of Pathogens

Schatzman

Culotta

2018

ACS Infect. Dis.

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Superoxide anion radical is generated as a natural byproduct of aerobic metabolism, but is also produced as part of the oxidative burst of the innate immune response design to kill pathogens. In living systems, superoxide is largely managed through superoxide dismutases (SODs), families of metalloenzymes that use Fe, Mn, Ni or Cu cofactors to catalyze the disproportionation of superoxide to oxygen and hydrogen peroxide. Given the bursts of superoxide faced by microbial pathogens, it comes as no surprise that SOD enzymes play important roles in microbial survival and virulence. Interestingly, microbial SOD enzymes not only detoxify host superoxide, but may also participate in signaling pathways that involve reactive oxygen species derived from the microbe itself, particularly in the case of eukaryotic pathogens. In this review, we will discuss the chemistry of superoxide radicals and the role of diverse SOD metalloenzymes in bacterial, fungal, and protozoan pathogens. We will highlight the unique features of microbial SOD enzymes that have evolved to accommodate the harsh lifestyle at the host-pathogen interface. Lastly, we will discuss key non-SOD superoxide scavengers that specific pathogens employ for defense against host superoxide.

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“…S1A). Zinc homeostasis is critical to the virulence of S. aureus (26) and of many other microbial pathogens, and allows the organism to adapt to host-imposed zinc toxicity or limitation (27,28). CzrA is a member of the ubiquitous arsenic repressor (ArsR) family of metalloregulatory proteins (25,29), individual members of which are capable of sensing a wide array of metal, metalloid, and nonmetal inducers on distinct sites on a relatively simple, homodimeric winged-helical scaffold (Fig.…”

mentioning

confidence: 99%

Entropy redistribution controls allostery in a metalloregulatory protein

Capdevila

Braymer

Edmonds

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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143

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Allosteric communication between two ligand-binding sites in a protein is a central aspect of biological regulation that remains mechanistically unclear. Here we show that perturbations in equilibrium picosecond-nanosecond motions impact zinc (Zn)-induced allosteric inhibition of DNA binding by the Zn efflux repressor CzrA (chromosomal zinc-regulated repressor). DNA binding leads to an unanticipated increase in methyl side-chain flexibility and thus stabilizes the complex entropically; Zn binding redistributes these motions, inhibiting formation of the DNA complex by restricting coupled fast motions and concerted slower motions. Allosterically impaired CzrA mutants are characterized by distinct nonnative fast internal dynamics "fingerprints" upon Zn binding, and DNA binding is weakly regulated. We demonstrate the predictive power of the wild-type dynamics fingerprint to identify key residues in dynamics-driven allostery. We propose that driving forces arising from dynamics can be harnessed by nature to evolve new allosteric ligand specificities in a compact molecular scaffold. Technological advances in structural biology have permitted insights (3-5) into how changes in protein structure and flexibility contribute to allostery (6-9). Allostery likely employs a continuum of mechanisms, from domain or subunit rearrangements to predominantly side-chain and backbone dynamics (6-8, 10, 11), to affect biological regulation (1). Although these motions clearly impact site-site communication via defined molecular pathways (9) or energy level perturbations at distant sites (12), an allosteric effect without conformational change remains largely a theoretical postulate (10,13,14). In this context, changes in dynamics upon ligand binding (8,(15)(16)(17)(18)(19)(20) have long been predicted to impact allostery (5, 14, 17, 21); however, obtaining a quantitative experimental demonstration of the role of conformational entropy in allosteric systems remains challenging. Here we test these ideas in the context of heterotropic linkage and pinpoint fast internal dynamics as a primary contributor to functional, structure-encoded dynamics. We report an example of allostery where side-chain rotamer degeneracy is largely responsible for coupling two ligand-binding events through perturbations in a dynamic network that is required for both entropic and enthalpic driving forces.Our model system for studying heterotropic allostery is the transcriptional regulator CzrA (chromosomal zinc-regulated repressor) from the bacterial pathogen Staphylococcus aureus (22-25) ( Fig. 1 and Fig. S1A). Zinc homeostasis is critical to the virulence of S. aureus (26) and of many other microbial pathogens, and allows the organism to adapt to host-imposed zinc toxicity or limitation (27, 28). CzrA is a member of the ubiquitous arsenic repressor (ArsR) family of metalloregulatory proteins (25, 29), individual members of which are capable of sensing a wide array of metal, metalloid, and nonmetal inducers on distinct sites on a relatively simple, homodimeric wi...

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Bacterial Strategies to Maintain Zinc Metallostasis at the Host-Pathogen Interface

Cited by 140 publications

References 100 publications

Metallochaperones and metalloregulation in bacteria

Metallochaperones and metalloregulation in bacteria

Chemical Warfare at the Microorganismal Level: A Closer Look at the Superoxide Dismutase Enzymes of Pathogens

Entropy redistribution controls allostery in a metalloregulatory protein

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