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Mechanisms of Zinc Metallostasis in Bacterial Pathogens
Author(s) -
Giedroc David,
Capdevila Daiana A.,
Martin Julia E.,
Edmonds Katherine A.,
Wu Hongwei
Publication year - 2017
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.31.1_supplement.406.2
Subject(s) - allosteric regulation , tetr , repressor , efflux , regulator , biology , biochemistry , atp binding cassette transporter , allosteric enzyme , transcription factor , chemistry , microbiology and biotechnology , transporter , gene , receptor
First‐row late d ‐block transition metals from Mn to Zn play critical and distinct roles in many aspects of cellular metabolism. In bacterial pathogens, metalloregulation of transcription underscores physiological adaptation to host‐mediated transition metal starvation and toxicity, required to maintain metal homeostasis. In zinc (Zn) homeostasis, a pair of metal‐sensing transcriptional repressors regulate the transcription of metal uptake and efflux transporters, where Zn typically allosterically activates or inhibits, respectively, DNA operator‐promoter binding. We have interests in the molecular underpinnings of allostery in metalloregulatory proteins, transition metal transporter function and the impact that dysregulation of the process has on cellular physiology. In the model Gram‐positive respiratory pathogen, Streptococcus pneumoniae , the Zn uptake regulator is the multiple antibiotic resistance repressor (MarR)‐family protein, adhesin‐competence repressor (AdcR), while the efflux regulator is a novel tetracycline repressor (TetR) family protein, streptococcal zinc activator (SczA). These are interesting regulatory targets with which to probe allosteric regulation of DNA binding by metals since in the vast majority of MarR and TetR repressors, the regulatory ligand functions as an allosteric inhibitor of DNA binding (+Δ G c ); in both AdcR and SczA, the sign on the allosteric coupling free energy, Δ G c , is negative or favorable. NMR solution structural studies of both backbone and methyl side‐chain flexibility as a function of allosteric state in AdcR will be discussed, as will NMR studies of AdcR‐regulated Zn uptake transporter, and the Zn efflux regulator SczA. In addition, recent findings of effect of host‐imposed Zn toxicity on pneumococcal physiology will also be presented. Support or Funding Information Supported by the US National Institutes of Health grant GM118157.