Article abstract
Nature Chemical Biology 3, 60 - 68 (2006)
Published online: 3 December 2006 | doi:10.1038/nchembio844
CsoR is a novel Mycobacterium tuberculosis copper-sensing transcriptional regulator
Tong Liu1,5, Arati Ramesh1,2,5, Zhen Ma1, Sarah K Ward3, Limei Zhang4, Graham N George4, Adel M Talaat3, James C Sacchettini1,2 & David P Giedroc1
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.
- Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843-2128, USA.
- Center for Structural Biology, Texas A&M University, College Station, Texas 77843-2128, USA.
- Department of Animal Health and Biomedical Sciences, University of Wisconsin, Madison, Wisconsin 53706, USA.
- Department of Geological Sciences, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E2, Canada.
- These authors contributed equally to this work.
Correspondence to: David P Giedroc1 e-mail: giedroc@tamu.edu
Correspondence to: James C Sacchettini1,2 e-mail: sacchett@tamu.edu
