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Abstract
Transcription factors are the primary regulators of gene expression and recognize specific DNA sequences under diverse physiological conditions. Although they are vital for many important cellular processes, it remains unclear when and how transcription factors and DNA interact. The antitoxin from a toxin-antitoxin system is an example of negative transcriptional autoregulation: during expression of the cognate toxin it is suppressed through binding to a specific DNA sequence. In the present study, the antitoxin HigA2 from Mycobacterium tuberculosis M37Rv was structurally examined. The crystal structure of M.tuberculosis HigA2 comprises three sections: an N-terminal autocleavage region, an α-helix bundle which contains an HTH motif, and a C-terminal β-lid. The N-terminal region is responsible for toxin binding, but was shown to cleave spontaneously in its absence. The HTH motif performs a key role in DNA binding, with the C-terminal β-lid influencing the interaction by mediating the distance between the motifs. However, M. tuberculosis HigA2 exhibits a unique coordination of the HTH motif and no DNA-binding activity is detected. Three crystal structures of M. tuberculosis HigA2 show a flexible alignment of the HTH motif, which implies that the motif undergoes structural rearrangement to interact with DNA. This study reveals the molecular mechanisms of how transcription factors interact with partner proteins or DNA.
Highlights
Bacterial gene regulation is controlled by a multitude of transcription factors that recognize specific DNA sequences and allow controlled cellular responses (Villard, 2004)
Due to a lack of electron density at the N-terminus, station at Pohang Light Source (PLS), Korea and the I04 $25 residues are undefined in each monomer despite the experimental station at Diamond Light Source (DLS), UK. relatively high resolution
While MtHigA2 and MtHigA3 use a C-terminal -lid for dimerization, P. aeruginosa HigA and P. vulgaris HigA utilize a long -helix and V. cholerae HigA uses a short -helix at the C-terminus for dimerization (Song et al, 2021; Schureck et al, 2019; Hadzi et al, 2017)
Summary
Bacterial gene regulation is controlled by a multitude of transcription factors that recognize specific DNA sequences and allow controlled cellular responses (Villard, 2004). Given their role in responding to environmental cues such as host colonization and virulence, transcription factors have been intensively studied as drug targets (Liu et al, 2015). The simplest motif, helix–turn–helix (HTH), comprises two -helices with a fixed angle permitting binding to the major groove of DNA (Luscombe et al, 2000). HTH motif-containing proteins typically form dimers that strengthen their DNA interaction and can mirror the dyad symmetry of their binding site (Brennan & Matthews, 1989)
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