PROSITE documentation PDOC00830

TetR-type HTH domain signature and profile

The tetR-type HTH domain is a DNA-binding, helix-turn-helix (HTH) domain of about 60 residues present in the tetR family of prokaryotic transcription regulators. Several of these bacterial regulators are repressors of genes and operons for membrane transport and cell envelope permeability. The family is named after the tetracycline repressor tetR of enterobacteria found on Tn10 and other transposons and plasmids. The 'helix-turn-helix' DNA-binding motif is located in the N-terminal extremity of these transcriptional regulators [1]. The C-terminal part of tetR-type regulators contains several regions that can be involved in (1) binding of inducers, which can be drugs, and (2) oligomerization. The tetR and camR proteins are dimers, whilst qacR binds its operator as a pair of dimers and ethR seems to bind as an octamer [2,3,4]. TetR-type transcription regulators include several bacterial regulators of drug export systems that protect pathogenic bacteria against antibiotics, antiseptics, disinfectants and host-encoded antimicrobials [3].

Several crystal structures of tetR-type transcription regulators have been resolved and their DNA-binding domains are formed by a three-helix bundle (H1-H3) and the N-terminal part of the following helix 4, which contributes to the hydrophobic center of the DNA-binding domain and links it to the regulatory domain [2]. The helix-turn-helix motif comprises the second and third helices, the third being called the recognition helix as it binds into the DNA major groove (see <PDB:1JT0>). The recognition helix of the tetR-type HTH is shorter than in most HTHs.

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

• Enterobacterial transposon and plasmid encoded tetR, a repressor of the tetracycline (Tc) exporting protein tetA. Binding of Tc in complex with Mg to tetR abolishes DNA binding to two palindromic operator sites tetO, upon which transcription of the tetA and tetR genes is initiated. This is the most common resistance mechanism against the antibiotic Tc in Gram-negative bacteria and commonly used as a gene-regulation tool in eukaryotes.
• Staphylococcus aureus plasmid encoded qacR, a multidrug binding repressor of the qacA multidrug resistance pump, which confers resistance to antiseptics and disinfectants such as QACs (quaternary ammonium compounds) [5].
• Escherichia coli acrR, a potential transcription repressor involved in the regulation of drug efflux operon acrAB.
• Pseudomonas putida plasmid encoded camR, a repressor of the cytochrome P-450cam hydroxylase operon, involved in the degradation of camphor.
• Escherichia coli betI, a choline-induced transcription regulator of the bet operon, involved in the choline-glycine βine pathway against osmotic stress.
• Neisseria gonorrhoeae mtrR, a repressor of the mtrCDE-encoded efflux pump system (for "multiple transferable resistance") and of the farR regulator, involved in regulation of the resistance to host-derived antimicrobial hydrophobic agents.
• Streptomyces glaucescens tcmR, a repressor of tcmR and tcmA, involved in resistance against the antibiotic tetracenomycin C.

As a signature pattern we selected a conserved region that starts six residues before the helix-turn-helix motif and ends seven residues after the H-T-H motif. We also developed a profile that covers the entire HTH and DNA-binding domain, from the first helix and including the major part of the fourth helix, and allows a more sensitive detection.