InterPro domain: IPR001845

The arsR-type HTH domain is a DNA-binding, winged helix-turn-helix (wHTH)domain present in transcription regulators of thearsR/smtB family, involved in stress-response to heavy metal ions. This familyof prokaryotic metal-sensing transcription repressors is named afterEscherichia coli arsR, an arsenic-responsive repressor of the ars operon forarsenate reductase and metal ion extrusion, and after Synechococcus PCC 7942smtB, a Zn(II)-responsive repressor of the smtA gene for a Zn sequesteringmetallothionein [ 1 ]. ArsR/smtB-like repressors of metal resistance operons specifically bind to the operator/promoter and seem to dissociate from the DNA in the presence of metal ions, permitting transcription of proteins involved in metal-ions efflux and/or detoxification.

The crystal structure of the cyanobacterial smtB shows a fold of fivealpha-helices (H) and a pair of antiparallel beta-strands (B) in the topologyH1-H2-H3-H4-B1-B2-H5. Helices 3 and 4 comprise thehelix-turn-helix motif and the beta-sheet is called the wing as in other wHTH,such as the dtxR-type or the merR-type.Helix 4 is termed the recognition helix, like in other HTHs where it binds theDNA major groove. Most arsR/smtB-like metalloregulators form homodimers [ 2 ].The dimer interface is formed by helix 5 and an N-terminal part [ 3 ]. Twodistinct metal-binding sites have been identified. The first site comprisescysteine thiolates located in the HTH in helix 3 and for some cases in theN terminus, called the alpha3(N) site [ 4 , 4 , 4 ]. The second metal-binding siteis located in helix 5 (and C terminus) and is called the alpha5(C) site. Thealpha3N site binds large thiophilic, toxic metals including Cd, Pb, and Bi, asin S. aureus cadC. ArsR lacks the N-terminal arm and its alpha3 sitecoordinates smaller thiophilic ions like As and Sb. The alpha5 site containscarboxylate and imidazole ligands and interacts preferentially withbiologically required metal ions including Zn, Co, and Ni. ArsR-typemetalloregulators contain one of these sites, both, or other potentialmetal-binding sites [ 5 , 5 ]. Binding of metal ions to these sites leads toallosteric changes that can derepress the operator/promoter DNA. Themetal-inducible operons contain one or two imperfect 12-2-12 inverted repeats,which can be recognised by multimeric arsR-type metalloregulators.

Some proteins known to contain an arsR-type HTH domain:

• Escherichia coli arsR, an arsenic-responsive transcription repressor of the arsenic resistance operon (ars) which encodes an arsenate reductase andmetal exporters.
• Synechococcus PCC 7942 smtB, a Zn(II)-responsive transcription repressor ofthe smtA gene that codes for a metallothionein. SmtB senses Co(II) and Cd(II) too, but Zn(II) is the preferred effector.
• Staphylococcus aureus cadC, a transcription regulator of the cadmiumresistance (cad) operon which encodes a Cd/Pb-specific efflux ATPase [ 6 ].
• Mycobacterium tuberculosis cmtR, a Pb(II)/Cd(II)-sensing repressor [ 7 ].

1. The SmtB/ArsR family of metalloregulatory transcriptional repressors: Structural insights into prokaryotic metal resistance. FEMS Microbiol. Rev. 27, 131-43
2. A metal-ligand-mediated intersubunit allosteric switch in related SmtB/ArsR zinc sensor proteins. J. Mol. Biol. 333, 683-95
3. Crystal structure of the cyanobacterial metallothionein repressor SmtB: a model for metalloregulatory proteins. J. Mol. Biol. 275, 337-46
4. A possible mechanism for metal-ion induced DNA-protein dissociation in a family of prokaryotic transcriptional regulators. Nucleic Acids Res. 21, 2515
5. A novel cyanobacterial SmtB/ArsR family repressor regulates the expression of a CPx-ATPase and a metallothionein in response to both Cu(I)/Ag(I) and Zn(II)/Cd(II). J. Biol. Chem. 279, 17810-8
6. CadC, the transcriptional regulatory protein of the cadmium resistance system of Staphylococcus aureus plasmid pI258. J. Bacteriol. 177, 4437-41
7. Structural and functional characterization of Mycobacterium tuberculosis CmtR, a PbII/CdII-sensing SmtB/ArsR metalloregulatory repressor. Biochemistry 44, 8976-88