PROSITE documentation PDOC00861

MarR-type HTH domain signature and profile

The marR-type HTH domain is a DNA-binding, winged helix-turn-helix (wHTH) domain of about 135 amino acids present in transcription regulators of the marR/slyA family, involved in the development of antibiotic resistance. This family of transcription regulators is named after Escherichia coli marR, a repressor of genes which activate the multiple antibiotic resistance and oxidative stress regulons, and after slyA from Salmonella typhimurium and E. coli, a transcription regulator that is required for virulence and survival in the macrophage environment. Regulators with the marR-type HTH domain are present in bacteria and archaea and control a variety of biological functions, including resistance to multiple antibiotics, household disinfectants, organic solvents, oxidative stress agents and regulation of the virulence factor synthesis in pathogens of humans and plants. Many of the marR-like regulators respond to aromatic compounds [1,2,3].

The crystal structures of marR, mexR and slyA have been determined and show a winged HTH DNA-binding core flanked by helices involved in dimerization (see <PDB:1LJ9>). The DNA-binding domains are ascribed to the superfamily of winged helix proteins, containing a three (four)-helix (H) bundle and a three-stranded antiparallel β-sheet (B) in the topology: H1-(H1')-H2-B1-H3-H4-B2-B3-H5-H6. Helices 3 and 4 comprise the helix-turn-helix motif and the β-sheet is called the wing. Helix 4 is termed the recognition helix, like in other HTHs where it binds the DNA major groove. The helices 1, 5 and 6 are involved in dimerization, as most marR-like transcription regulators form dimers [3,4,5].

Some proteins known to contain a marR-type HTH domain:

• Escherichia coli marR, a transcription repressor of chromosomal multiple antibiotic resistance (mar) in diverse bacteria [1,4].
• Salmonella typhimurium and E. coli slyA, a transcription activator for molecular chaperones, proteins involved in acid resistance and in virulence and a repressor for the expression of several biosynthetic enzymes.
• Pseudomonas aeruginosa mexR, a transcription repressor of the mexAB-oprM multidrug efflux operon, a major determinant for broad resistance. The allosteric mechanism for the regulation of DNA binding seems to differ from that of marR [5].
• Rhodopseudomonas palustris badR, a transcription activator for the anaerobic degradation of benzoate [2].
• Escherichia coli mprA (emrR), a repressor of the multidrug resistance pump emrAB operon.
• Erwinia chrysanthemi pecS, a transcription regulator for synthesis of pectinase, cellulase and other key factors for plant infection.
• Bacillus subtilis hpr, a repressor of protease production and sporulation.
• Butyrivibrio fibrisolvens cinR, a transcription repressor of cinnamoyl ester hydrolase for ruminal degradation of plant material.

As a signature pattern, we have selected a 34 residue segment showing high conservation within this family. This conserved region from helix 3 to strand 3 is located in the DNA binding domain. We also developed a profile that covers the entire wHTH, including helix 1 and the conserved part of helix 6, and which allows a more sensitive detection.