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Structure, Function and Mechanism of AztD, a Zinc Metallochaperone
Author(s) -
Yukl Erik T.,
Neupane Durga Prasad,
Fullam Stephanie,
Chacón Kelly
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.02353
Subject(s) - periplasmic space , atp binding cassette transporter , operon , permease , zinc , biochemistry , biology , membrane transport protein , microbiology and biotechnology , chemistry , transporter , gene , mutant , escherichia coli , organic chemistry
Zinc is an essential element that is toxic in excess. Thus, zinc homeostasis is a critical function for all organisms. In bacteria, it is generally maintained by transcriptional regulation of zinc import and export proteins by zinc‐responsive transcriptional regulators. Disruption of zinc homeostasis in bacterial pathogens can result in dramatic attenuation of virulence, making these systems potential targets for the development of novel antibiotics. In particular, zinc importers of the ATP binding cassette (ABC) type are critical for the survival of many bacteria under zinc starvation conditions. Bacterial ABC transporters rely on a periplasmic or lipoprotein solute binding protein (SBP) to bind zinc with high affinity and specificity and deliver it to the membrane permease for import into the cytoplasm. Recently, the participation of other extracellular zinc‐binding proteins (e.g. metallochaperones) in metal import through ABC transporters has been demonstrated in some species. We are studying zinc homeostasis in Paracoccus denitrificans , an organism with two zinc‐specific ABC transporter operons znuABC and aztABCD . These are under transcriptional control of the zinc uptake regulator (Zur), are highly upregulated during zinc deprivation, and are required for normal growth under these conditions. Further, both operons are highly conserved in several human pathogens, including Klebsiella pneumoniae , a member of the carbapenem‐resistant Enterobacteriaceae (CRE) considered an “Urgent Threat” by the Centers for Disease Control. The aztABCD operon encodes a periplasmic metallochaperone (AztD) capable of transferring zinc to the associated SBP (AztC) through a specific, associative mechanism that can be followed in vitro using intrinsic tryptophan fluorescence. Crystal structures of AztD and AztC combined with kinetic data and mutational studies are beginning to reveal the function of AztD in zinc homeostasis and the molecular mechanism of zinc transfer. The observation that AztD is conserved in more than 500 genomes from diverse bacterial taxa suggests that this protein is an important component of zinc homeostasis and a newly identified family of zinc metallochaperones. Support or Funding Information National Institutes of Health 1R01GM122819‐01A1Docking model of the zinc transfer complex between the metallochaperone AztD (green) and the solute binding protein AztC (magenta)