TetR Regulators: A Structural and Functional Perspective

Abstract

Tetracycline repressor family of transcription regulators (TetRFTRs)
is one of the most predominant families of transcription factors in
the prokaryotic system. Classically, they are associated with antimicrobial
resistance since they regulate the genes encoding the efflux pumps
that export antibiotics out of the cell. Analysis shows that TetR-FTRs
adopt a broader role in bacterial function than earlierly envisioned. Apart
from efflux of antibiotics these proteins also regulate pathways associated
with cell–cell signaling, antibiotic biosynthesis, biofilm formation,
etc. Furthermore, an in-depth scrutiny of the available three-dimensional
structures of TetR-FTRs and comparison of their various forms (apo,
liganded and DNA-bound) helped to obtain valuable insights into the
underlying molecular mechanism of action. TetR-FTRs possess a modular
architecture with the N-terminal DNA-binding domain comprising
canonical DNA-binding helix-turn-helix motif that is mostly conserved,
whereas, the C-terminal signal reception domain is evolutionarily more
diverse as it is tailored to accept the appropriate ligand. The TetR-FTRs
serve as repressors when bound to their target DNA sequence, in the
absence of their signaling molecule. On ligand binding, de-repression
occurs by the coordinated motions of helices at the interface of the two
domains. The DNA-binding domain undergoes a pendulum-like shift
along the connecting helix, α4, and this motion transmits the signal.
Overall, an understanding of the allosteric mechanism allows these proteins
to switch from one state to another, an important transformation of
their regulatory function.