Structural basis of operator sites recognition and effector binding in the TetR family transcription regulator FadR

Abstract

FadR is a fatty acyl-CoA dependent transcription factor that regulates genes encoding proteins involved in fatty-acid degradation and synthesis pathways. In this study, the crystal structures of Bacillus halodurans FadR, which belong to the TetR family, have been determined in three different forms: ligand-bound, ligand-free and DNA-bound at resolutions of 1.75, 2.05 and 2.80 Å, respectively. Structural and functional data showed that B. halodurans FadR was bound to its operator site without fatty acyl-CoAs. Structural comparisons among the three different forms of B. halodurans FadR revealed that the movement of DNA binding domains toward the operator DNA was blocked upon binding of ligand molecules. These findings suggest that the TetR family FadR negatively regulates the genes involved in fatty acid metabolism by binding cooperatively to the operator DNA as a dimer of dimers.

Mycobacterium tuberculosis FasR senses long fatty acyl-CoA through a tunnel and a hydrophobic transmission spine

“…Correlated to this HTH movement and again transmitted through the hydrophobic spine, several of the bulky residues that line up the effector-binding cavity walls, occlude the cavity (such as Phe 123 in FasR–DNA), completing the spine into a “folded protein-like” core. This occlusion of the ligand-binding pocket in other TFRs when bound to DNA has been described in crystal structures of TetR 29 , DesT 22 and FadR 23 .…”

“…4 , Supplementary Movie 1 ). Other fatty acid-sensory TFRs fairly similar to FasR 18 , 21 – 23 , either do not create true continuous tunnels 22 , or engage a different set of residues running in a perpendicular direction as compared with FasR’s cavity 18 , 21 , 23 . EthR is yet another TFR from Mtb 24 , intensively investigated as a target to develop anti-tuberculosis medicines.…”

Functional Mechanism of the Efflux Pumps Transcription Regulators From Pseudomonas aeruginosa Based on 3D Structures

“…This amino acid is often a short one (Ramos et al, 2005 ). In the case of FadR, a regulator involved in the fatty-acid degradation and synthesis pathways, mutation of each of these two conserved residues led to a significant reduction of DNA binding as proved by electrophoretic mobility shift assays (Yeo et al, 2017 ). It seems that the regulator could slide on the DNA until the α3 helix recognizes the cognate sequence, using a short residue at position Y-4 to enter more deeply into the groove.…”

Effect of the TetR family transcriptional regulator Sp1418 on the global metabolic network of Saccharopolyspora pogona

“…Currently, a substantial number of proteins have been reported to regulate the metabolites of bacteria [10][11][12], including some global regulators [13,14], which are of great significance in growth, phenotype and metabolism. TetR family regulators have been reported in numerous organisms [15,16]; they are involved in the regulating biosynthesis of antibiotics, efflux pumps, osmotic stress, etc., and typically function as repressors [17] to regulate the expression of genes, such as the ameABC operon [18] and fadR operator [19].…”