MarR family transcription factors: dynamic variations on a common scaffold

Abstract

Members of the multiple antibiotic resistance regulator (MarR) family of transcription factors are critical for bacterial cells to respond to chemical signals and to convert such signals into changes in gene activity. Obligate dimers belonging to the winged helix-turn-helix protein family, they are critical for regulation of a variety of functions, including degradation of organic compounds and control of virulence gene expression. The conventional regulatory paradigm is based on a genomic locus in which the gene encoding the MarR protein is divergently oriented from a gene under its control; MarR binding to the intergenic region controls expression of both genes by changing the interaction of RNA polymerase with gene promoters. MarR protein oxidation or binding of a small molecule ligand adversely affects DNA binding, resulting in altered expression of the divergent genes. The generality of this simple paradigm, including the regulation of Escherichia coli MarR by direct binding of antibiotics, has been challenged by reports published in recent years. In addition, structural and biochemical analyses of ligand binding to numerous MarR homologs are converging to identify a shared ligand-binding "hot-spot". This review highlights recent research advances that point to shared features, yet at the same time highlights the remarkable flexibility with which members of this protein family implement responses to inducing signals. A more comprehensive understanding of protein function will pave the way towards the development of both antibacterial agents and biosensors that are based on MarR family proteins.

Global Awakening of Cryptic Biosynthetic Gene Clusters in Burkholderia thailandensis

“…While several bacterial species encode transcription factors that share homology with MftR, including the ability to bind urate, 19–21 MftR is mainly encoded by Burkholderia species (Fig. S1).…”

Structural insights into repression of the Pneumococcal fatty acid synthesis pathway by repressor FabT and co‐repressor acyl‐ACP

“…S. pneumoniae employs FabT, a MarR family transcription factor, to globally regulate the FAS pathway [23]. Usually, the DNA-binding affinity of MarR family members are subject to regulation via diverse small ligands, such as phenolic molecules and metals, or of post-translational modifications, resulting in upregulation of related genes in most cases [43]. The family was originally named after E. coli MarR, a repressor of the marRAB operon, the products of which confer resistance to multiple antibiotics and household disinfectants [49].…”

“…2B). Indeed, mutation of the conserved residue Arg89 resulted in a decreased DNA-binding affinity [43]. 2B).…”

MarR family proteins are important regulators of clinically relevant antibiotic resistance

“…However, with widespread use of broad spectrum antibiotics such as the carbapenems, there has been a recent emergence of bacteria with reduced outer membrane permeability and in which further active efflux of drug contributes significantly to increased MICs . One critical family of these multidrug‐binding, efflux‐pump regulators is the MarR family, which is named after its founding member, the Escherichia coli M ultiple a ntibiotic r esistance R epressor (MarR) …”

“…MepR is a functional homodimer with each subunit containing six alpha helices and a two‐stranded antiparallel β‐hairpin . MepR lacks the third β‐strand between helices α2 and α3 that is common to other wHTH MarR family members . A key structural feature of MepR, related to its function as a multidrug‐binding transcription regulator, is the conformational plasticity of helices α1, α5 and α6, which is also a likely component of its allosteric induction mechanism …”