期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 288, 期 2, 页码 1286-1294出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.421008
关键词
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资金
- National Science Foundation-CAREER Award [MCB-0952550]
- National Institutes of Health-NINDS Predoctoral Fellowship Award [F31NS062630]
- National Science Foundation-Experimental Program to Stimulate Competitive Research (EPSCoR) graduate fellowship
- National Science Foundation-EPSCoR [1004057, 0554548]
- National Institutes of Health [1S10RR020923]
- Rhode Island Science and Technology Advisory Council grant
- Division of Biology and Medicine, Brown University
- National Institutes of Health (NCRR) [P30RR031153, P20RR018728, S10RR02763]
- Lifespan Rhode Island Hospital
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [0952550] Funding Source: National Science Foundation
- Office of Integrative Activities
- Office Of The Director [1004057] Funding Source: National Science Foundation
Bacterial biofilms are complex communities of cells containing an increased prevalence of dormant cells known as persisters, which are characterized by an up-regulation of genes known as toxin-antitoxin (TA) modules. The association of toxins with their cognate antitoxins neutralizes toxin activity, allowing for normal cell growth. Additionally, protein antitoxins bind their own promoters and repress transcription, whereas the toxins serve as co-repressors. Recently, TA pairs have been shown to regulate their own transcription through a phenomenon known as conditional cooperativity, where the TA complexes bind operator DNA and repress transcription only when present in the proper stoichiometric amounts. The most differentially up-regulated gene in persister cells is mqsR, a gene that, with the antitoxin mqsA, constitutes a TA module. Here, we reveal that, unlike other TA systems, MqsR is not a transcription co-repressor but instead functions to destabilize the MqsA-DNA complex. We further show that DNA binding is not regulated by conditional cooperativity. Finally, using biophysical studies, we show that complex formation between MqsR and MqsA results in an exceptionally stable interaction, resulting in a subnanomolar dissociation constant that is similar to that observed between MqsA and DNA. In combination with crystallographic studies, this work reveals that MqsA binding to DNA and MqsR is mutually exclusive. To our knowledge, this is the first TA system in which the toxin does not function as a transcriptional co-repressor, but instead functions to destabilize the antitoxin-operator complex under all conditions, and thus defines another unique feature of the mqsRA TA module.
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