CsoR is a novel Mycobacterium tuberculosis copper-sensing transcriptional regulator

Tong Liu, Arati Ramesh, Zhen Ma, Sarah K. Ward, Limei Zhang, Graham N. George, Adel M. Talaat, James C. Sacchettini, David P. Giedroc

Research output: Contribution to journalArticle

223 Scopus citations

Abstract

Copper is an essential element that becomes highly cytotoxic when concentrations exceed the capacity of cells to sequester the ion. Here, we identify a new copper-specific repressor (CsoR) of a copper-sensitive operon (cso) in Mycobacterium tuberculosis (Mtb) that is representative of a large, previously uncharacterized family of proteins (DUF156). Electronic and X-ray absorption spectroscopies reveal that CsoR binds a single-monomer mole equivalent of Cu(I) to form a trigonally coordinated (S2N) Cu(I) complex. The 2.6-Å crystal structure of copper-loaded CsoR shows a homodimeric antiparallel four-helix bundle architecture that represents a novel DNA-binding fold. The Cu(I) is coordinated by Cys36, Cys65′ and His61′ in a subunit bridging site. Cu(I) binding negatively regulates the binding of CsoR to a DNA fragment encompassing the operator-promoter region of the Mtb cso operon; this results in derepression of the operon in Mtb and the heterologous host Mycobacterium smegmatis. Substitution of Cys36 or His61 with alanine abolishes Cu(I)- and CsoR-dependent regulation in vivo and in vitro. Potential roles of CsoR in Mtb pathogenesis are discussed.

Original languageEnglish (US)
Pages (from-to)60-68
Number of pages9
JournalNature Chemical Biology
Volume3
Issue number1
DOIs
StatePublished - Jan 2007

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Liu, T., Ramesh, A., Ma, Z., Ward, S. K., Zhang, L., George, G. N., Talaat, A. M., Sacchettini, J. C., & Giedroc, D. P. (2007). CsoR is a novel Mycobacterium tuberculosis copper-sensing transcriptional regulator. Nature Chemical Biology, 3(1), 60-68. https://doi.org/10.1038/nchembio844