The SmtB/ArsR family of metalloregulatory transcriptional repressors: structural insights into prokaryotic metal resistance

• Published in: FEMS microbiology reviews 2003-06, Vol.27 (2), p.131-143
• Main Authors: Busenlehner, Laura S., Pennella, Mario A., Giedroc, David P.
• Format: Article
• Language: English
• Subjects: Allosteric properties; Amino Acid Sequence; Bacterial Proteins; Base Sequence; Binding; Binding Sites; CadC; Cadmium; Coordination compounds; CzrA; Derepression; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - metabolism; Drug Resistance, Bacterial; E coli; Escherichia coli Proteins; Gene Expression Regulation, Bacterial; Heavy metal resistance; Heavy metals; Helices; Histidine; Ions; Lead; Ligands; Listeria; Listeria monocytogenes; Metal complexes; Metal concentrations; Metal ions; Metalloregulation; Metals - metabolism; Metals - pharmacology; Models, Genetic; Molecular Sequence Data; Nickel; Operon; Operons; Pollutants; Protein structure; Repressor Proteins - chemistry; Repressor Proteins - metabolism; Repressors; Secondary structure; Selectivity; Sensors; Sequence Alignment; SmtB; Trans-Activators - chemistry; Trans-Activators - metabolism; Transcription factors; Transcription, Genetic; Tuberculosis; Zinc
• ISSN: 0168-6445; 1574-6976; 1574-6976
• DOI: 10.1016/S0168-6445(03)00054-8

The SmtB/ArsR family of prokaryotic metalloregulatory transcriptional repressors represses the expression of operons linked to stress-inducing concentrations of di- and multivalent heavy metal ions. Derepression results from direct binding of metal ions by these homodimeric ‘metal sensor’ proteins. An evolutionary analysis, coupled with comparative structural and spectroscopic studies of six SmtB/ArsR family members, suggests a unifying ‘theme and variations’ model, in which individual members have evolved distinct metal selectivity profiles by alteration of one or both of two structurally distinct metal coordination sites. These two metal sites are designated α3N (or α3) and α5 (or α5C), named for the location of the metal binding ligands within the known or predicted secondary structure of individual family members. The α3N/α3 sensors, represented by Staphylococcus aureus pI258 CadC, Listeria monocytogenes CadC and Escherichia coli ArsR, form cysteine thiolate-rich coordination complexes (S 3 or S 4) with thiophilic heavy metal pollutants including Cd(II), Pb(II), Bi(III) and As(III) via inter-subunit coordination by ligands derived from the α3 helix and the N-terminal ‘arm’ (CadCs) or from the α3 helix only (ArsRs). The α5/α5C sensors Synechococcus SmtB, Synechocystis ZiaR, S. aureus CzrA, and Mycobacterium tuberculosis NmtR form metal complexes with biologically required metal ions Zn(II), Co(II) and Ni(II) characterized by four or more coordination bonds to a mixture of histidine and carboxylate ligands derived from the C-terminal α5 helices on opposite subunits. Direct binding of metal ions to either the α3N or α5 sites leads to strong, negative allosteric regulation of repressor operator/promoter binding affinity, consistent with a simple model for derepression. We hypothesize that distinct allosteric pathways for metal sensing have co-evolved with metal specificities of distinct α3N and α5 coordination complexes.