title: CsoR is a novel Mycobacterium tuberculosis copper-sensing transcriptional regulator.
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 (S(2)N) Cu(I) complex. The 2.6-A 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.
authors.affiliation: Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843-2128, USA.
authors.forename: Tong
authors.initials: T
authors.lastname: Liu
authors.forename: Arati
authors.initials: A
authors.lastname: Ramesh
authors.forename: Zhen
authors.initials: Z
authors.lastname: Ma
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Ward
authors.forename: Limei
authors.initials: L
authors.lastname: Zhang
authors.forename: Graham N
authors.initials: GN
authors.lastname: George
authors.forename: Adel M
authors.initials: AM
authors.lastname: Talaat
authors.forename: James C
authors.initials: JC
authors.lastname: Sacchettini
authors.forename: David P
authors.initials: DP
authors.lastname: Giedroc
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D003300:Copper / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity; D018360:Crystallography, X-Ray; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects* / Q000235:genetics; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D009876:Operon / Q000187:drug effects / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D013057:Spectrum Analysis; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D014965:X-Rays
chemical_list: D001426:Bacterial Proteins; C517445:CsoR protein, Mycobacterium tuberculosis; D014157:Transcription Factors; D003300:Copper