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Journal of Bacteriology, June 2005, p. 4214-4221, Vol. 187, No. 12
0021-9193/05/$08.00+0     doi:10.1128/JB.187.12.4214-4221.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Crystal Structure of the Staphylococcus aureus pI258 CadC Cd(II)/Pb(II)/Zn(II)-Responsive Repressor

Jun Ye,{dagger} Ashoka Kandegedara,{dagger} Philip Martin, and Barry P. Rosen*

Department of Biochemistry and Molecular Biology, Wayne State University, School of Medicine, Detroit, Michigan 48201

Received 24 December 2004/ Accepted 22 February 2005

The Staphylococcus aureus plasmid pI258 cadCA operon encodes a P-type ATPase, CadA, that confers resistance to the heavy metals Cd(II), Zn(II), and Pb(II). Expression of this heavy-metal efflux pump is regulated by CadC, a homodimeric repressor that dissociates from the cad operator/promoter upon binding of Cd(II), Pb(II), or Zn(II). CadC is a member of the ArsR/SmtB family of metalloregulatory proteins. Here we report the X-ray crystal structure of CadC at 1.9 Å resolution. The dimensions of the protein dimer are approximately 30 Å by 40 Å by 70 Å. Each monomer contains six {alpha}-helices and a three-stranded ß-sheet. Helices 4 and 5 form a classic helix-turn-helix motif that is the putative DNA binding region. The {alpha}1 helix of one monomer crosses the dimer to approach the {alpha}4 helix of the other monomer, consistent with the previous proposal that these two regulatory metal binding sites for the inducer cadmium or lead are each formed by Cys-7 and Cys-11 from the N terminus of one monomer and Cys-58 and Cys-60 of the other monomer. Two nonregulatory metal binding sites containing zinc are formed between the two antiparallel {alpha}6 helices at the dimerization interface. This is the first reported three-dimensional structure of a member of the ArsR/SmtB family with regulatory metal binding sites at the DNA binding domain and the first structure of a transcription repressor that responds to the heavy metals Cd(II) and Pb(II).

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, Wayne State University, School of Medicine, 540 E. Canfield Ave., Detroit, MI 48201. Phone: (313) 577-1512. Fax: (313) 577-2765. E-mail: brosen{at}med.wayne.edu.

{dagger} J.Y. and A.K. contributed equally to this study.

Journal of Bacteriology, June 2005, p. 4214-4221, Vol. 187, No. 12
0021-9193/05/$08.00+0     doi:10.1128/JB.187.12.4214-4221.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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