期刊
NATURE CHEMICAL BIOLOGY
卷 3, 期 1, 页码 60-68出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nchembio844
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资金
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [P01AI068135] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM057375, T32GM007215, R29GM042569, R01GM042569] Funding Source: NIH RePORTER
- NIAID NIH HHS [AI068135] Funding Source: Medline
- NIGMS NIH HHS [T32 GM007215, GM057375, GM042569] Funding Source: Medline
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-angstrom 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.
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