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The zinc efflux activator S cz A protects S treptococcus pneumoniae serotype 2 D 39 from intracellular zinc toxicity
Author(s) -
Martin Julia E.,
Edmonds Katherine A.,
Bruce Kevin E.,
Campanello Gregory C.,
Eijkelkamp Bart A.,
Brazel Erin B.,
McDevitt Christopher A.,
Winkler Malcolm E.,
Giedroc David P.
Publication year - 2017
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1111/mmi.13654
Subject(s) - biology , tetr , zinc , microbiology and biotechnology , efflux , zinc toxicity , zinc finger , biochemistry , repressor , gene expression , transcription factor , chemistry , gene , organic chemistry
Summary Zinc is an essential trace element that serves as a catalytic cofactor in metalloenzymes and a structural element in proteins involved in general metabolism and cellular defenses of pathogenic bacteria. Despite its importance, high zinc levels can impair cellular processes, inhibiting growth of many pathogenic bacteria, including the major respiratory pathogen Streptococcus pneumoniae . Zinc intoxication is prevented in S. pneumoniae by expression of the zinc exporter CzcD, whose expression is activated by the novel TetR‐family transcriptional zinc‐sensing regulator SczA. How zinc bioavailability triggers activation of SczA is unknown. It is shown here through functional studies in S. pneumoniae that an unannotated homodimeric TetR from S. agalactiae (PDB 3KKC) is the bona fide zinc efflux regulator SczA, and binds two zinc ions per protomer. Mutagenesis analysis reveals two metal binding sites, termed A and B, located on opposite sides of the SczA C‐terminal regulatory domain. In vivo , the A‐ and B‐site SczA mutant variants impact S. pneumoniae resistance to zinc toxicity and survival in infected macrophages. A model is proposed for S. pneumoniae SczA function in which both A‐ and B‐sites were required for transcriptional activation of czcD expression, with the A‐site serving as the evolutionarily conserved intracellular sensing site in SczAs.