期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 293, 期 50, 页码 19429-19440出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA118.005173
关键词
structural biology; X-ray crystallography; DNA-binding protein; protein-protein interaction; bacterial toxin; antibiotic resistance; conditional cooperativity; HicAB; persistence; toxin-antitoxin system; type II TA system
资金
- Biotechnology and Biological Sciences Research Council-funded South West Biosciences Doctoral Training Partnership Training Grant [BB/J014400/1]
- BBSRC [BB/L01386X/1] Funding Source: UKRI
- EPSRC [EP/K03927X/1] Funding Source: UKRI
- Engineering and Physical Sciences Research Council [EP/K03927X/1] Funding Source: researchfish
Toxin-antitoxin (TA) systems are present in many bacteria and play important roles in bacterial growth, physiology, and pathogenicity. Those that are best studied are the type II TA systems, in which both toxins and antitoxins are proteins. The HicAB system is one of the prototypic TA systems, found in many bacterial species. Complex interactions between the protein toxin (HicA), the protein antitoxin (HicB), and the DNA upstream of the encoding genes regulate the activity of this system, but few structural details are available about how HicA destabilizes the HicB-DNA complex. Here, we determined the X-ray structures of HicB and the HicAB complex to 1.8 and 2.5 angstrom resolution, respectively, and characterized their DNA interactions. This revealed that HicB forms a tetramer and HicA and HicB form a heterooctameric complex that involves structural reorganization of the C-terminal (DNA-binding) region of HicB. Our observations indicated that HicA has a profound impact on binding of HicB to DNA sequences upstream of hicAB in a stoichiometric-dependent way. At low ratios of HicA:HicB, there was no effect on DNA binding, but at higher ratios, the affinity for DNA declined cooperatively, driving dissociation of the HicA:HicB:DNA complex. These results reveal the structural mechanisms by which HicA de-represses the HicB-DNA complex.
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