NDLI: Structural analyses of the MazEF4 toxin-antitoxin pair in Mycobacterium tuberculosis provide evidence for a unique extracellular death factor

Content Provider	Journal of Biological Chemistry (JBC)
Author	Ahn, Do-Hwan Lee, Ki-Young Lee, Sang Jae Park, Sung Jean Yoon, Hye-Jin Kim, Soon-Jong Lee, Bong-Jin
Abstract	The bacterial toxin-antitoxin MazEF system in the tuberculosis (TB)-causing bacterium Mycobacterium tuberculosis is activated under unfavorable conditions, including starvation, antibiotic exposure, and oxidative stress. This system contains the ribonucleolytic enzyme MazF and has emerged as a promising drug target for TB treatments targeting the latent stage of M. tuberculosis infection and reportedly mediates a cell death process via a peptide called extracellular death factor (EDF). Although it is well established that the increase in EDF-mediated toxicity of MazF drives a cell-killing phenomenon, the molecular details are poorly understood. Moreover, the divergence in sequences among reported EDFs suggests that each bacterial species has a unique EDF. To address these open questions, we report here the structures of MazF4 and MazEF4 complexes from M. tuberculosis, representing the first MazEF structures from this organism. We found that MazF4 possesses a negatively charged MazE4-binding pocket in contrast to the positively charged MazE-binding pockets in homologous MazEF complex structures from other bacteria. Moreover, using NMR spectroscopy and biochemical assays, we unraveled the molecular interactions of MazF4 with its RNA substrate and with a new EDF homolog originating from M. tuberculosis. The EDF homolog discovered here possesses a positively charged residue at the C terminus, making this EDF distinct from previously reported EDFs. Overall, our results suggest that M. tuberculosis evolved a unique MazF and EDF and that the distinctive EDF sequence could serve as a starting point for designing new anti-tuberculosis drugs. We therefore conclude that this study might contribute to the development of a new line of anti-tuberculosis agents.
Related Links	http://www.jbc.org/content/292/46/18832.abstract
Ending Page	18847
Starting Page	18832
Page Count	16
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	46
Volume Number	292
DOI	10.1074/jbc.M117.807974
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2017-11-17
Access Restriction	Open
Subject Keyword	Mycobacterium tuberculosis Nuclear magnetic resonance (NMR) Protein structure Quorum sensing X-ray crystallography MazEF system Extracellular death factor Toxin-antitoxin system Molecular Biophysics
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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