Mol Microbiol. 2017 Mar 1. doi: 10.1111/mmi.13654. [Epub ahead of print]

The zinc efflux activator SczA protects Streptococcus pneumoniae serotype 2 D39 from intracellular zinc toxicity.

Martin JE1, Edmonds KA1, Bruce KE2, Campanello GC1, Eijkelkamp BA3, Brazel EB3, McDevitt CA3, Winkler ME2, Giedroc DP1.

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Abstract

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. We show 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. We propose a model for S. pneumoniae SczA function in which both A- and B-sites are required for transcriptional activation of czcD expression, with the A-site serving as the evolutionarily conserved intracellular sensing site in SczAs. This article is protected by copyright. All rights reserved.

© 2017 John Wiley & Sons Ltd.

PMID: 28249108