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Structural determination of toxin-antitoxin system from Shigella flexneri
- Subtitle
- conformational changes of antitoxin HigA by binding of toxin HigB
- Author(s)
- 윤원수
- Advisor
- 서민덕
- Department
- 일반대학원 분자과학기술학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2021-02
- Language
- eng
- Keyword
- Shigella flexneri; Toxin-antitoxin
- Alternative Abstract
- Bacterial toxin-antitoxin systems are known to play an essential role in maintaining cells when they are in a difficult environment such as malnutrition, antibiotic treatment, and oxidative stress. There are six kinds of toxin-antitoxin systems according to the toxin-neutralizing mechanism of antitoxin. The type II toxin-antitoxin system which has been the most studied consists of a relatively unstable antitoxin protein and a stable toxin protein. In a normal cellular environment, toxin and antitoxin form a stable complex, which results in neutralization of toxin by antitoxin. However, when cells are placed in barren environments relatively unstable antitoxins are degraded by specific proteolytic enzymes, and free toxins show toxic activities causing cell death or growth inhibition. In the type II toxin-antitoxin system, antitoxin contains a DNA binding domain and it binds to a specific sequence in the promoter region to regulate the transcription of toxins and antitoxins. In this study, we have determined the crystal structures of antitoxin HigA from Shigella flexneri (SfHigA) and toxin-antitoxin complex HigBA from Shigella flexneri (SfHigBA). Apo-SfHigA adopts a V-shaped homodimer formed by N-terminal dimerization. Through structural comparison with known HigA structures, it could be predicted that DNA would bind through the HTH (helix-turn-helix) motif in the C-terminal region of the antitoxin SfHigA. SfHigBA appears as a heterotetramer formed by N-terminal dimerization of SfHigB-bound SfHigA molecules. When SfHigB binds, the structural change of SfHigA is mediated by rigid-body movements of the C-domain accompanied by a conformational change from a wide V-shaped to a narrow V-shaped dimer. As a result, two putative DNA binding helices (α7, α7’) are rearranged in a form that is more compatible with the standard homodimeric DNA binding protein containing the HTH motif. In addition, when SfHigB was bound, the structural changes of the C-domain of SfHigA results in a different DNA binding ability. The DNA binding affinity of SfHigBA, a toxin-antitoxin complex, was higher than that of apo- SfHigA. The structures of apo-SfHigA and SfHigBA covered in this study are expected to contribute to elucidating the biological function of TA system and also developing the antibiotics to overcome the drug tolerance.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Molecular Science and Technology > 4. Theses(Ph.D)
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