Disrupting coupling within mycobacterial F-ATP synthases subunit ε causes dysregulated energy production and cell wall biosynthesis
The dynamic interaction of the N- and C-terminal domains of mycobacterial F-ATP synthase subunit ε is proposed to contribute to efficient coupling of H+-translocation and ATP synthesis. Here, we investigate crosstalk between both subunit ε domains by introducing chromosomal atpC missense mutations i...
| Main Authors: | , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
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2020
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/138536 |
| _version_ | 1811690188224593920 |
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| author | Saw, Wuan-Geok Wu, Mu-Lu Ragunathan, Priya Biuković, Goran Lau, Aik-Meng Shin, Joon Harikishore, Amaravadhi Cheung, Chen-Yi Hards, Kiel Sarathy, Jickky Palmae Bates, Roderick Wayland Cook, Gregory M. Dick, Thomas Grüber, Gerhard |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Saw, Wuan-Geok Wu, Mu-Lu Ragunathan, Priya Biuković, Goran Lau, Aik-Meng Shin, Joon Harikishore, Amaravadhi Cheung, Chen-Yi Hards, Kiel Sarathy, Jickky Palmae Bates, Roderick Wayland Cook, Gregory M. Dick, Thomas Grüber, Gerhard |
| author_sort | Saw, Wuan-Geok |
| collection | NTU |
| description | The dynamic interaction of the N- and C-terminal domains of mycobacterial F-ATP synthase subunit ε is proposed to contribute to efficient coupling of H+-translocation and ATP synthesis. Here, we investigate crosstalk between both subunit ε domains by introducing chromosomal atpC missense mutations in the C-terminal helix 2 of ε predicted to disrupt inter domain and subunit ε-α crosstalk and therefore coupling. The ε mutant εR105A,R111A,R113A,R115A (ε4A) showed decreased intracellular ATP, slower growth rates and lower molar growth yields on non-fermentable carbon sources. Cellular respiration and metabolism were all accelerated in the mutant strain indicative of dysregulated oxidative phosphorylation. The ε4A mutant exhibited an altered colony morphology and was hypersusceptible to cell wall-acting antimicrobials suggesting defective cell wall biosynthesis. In silico screening identified a novel mycobacterial F-ATP synthase inhibitor disrupting ε’s coupling activity demonstrating the potential to advance this regulation as a new area for mycobacterial F-ATP synthase inhibitor development. |
| first_indexed | 2024-10-01T06:00:01Z |
| format | Journal Article |
| id | ntu-10356/138536 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:00:01Z |
| publishDate | 2020 |
| record_format | dspace |
| spelling | ntu-10356/1385362023-02-28T16:57:36Z Disrupting coupling within mycobacterial F-ATP synthases subunit ε causes dysregulated energy production and cell wall biosynthesis Saw, Wuan-Geok Wu, Mu-Lu Ragunathan, Priya Biuković, Goran Lau, Aik-Meng Shin, Joon Harikishore, Amaravadhi Cheung, Chen-Yi Hards, Kiel Sarathy, Jickky Palmae Bates, Roderick Wayland Cook, Gregory M. Dick, Thomas Grüber, Gerhard School of Biological Sciences School of Physical and Mathematical Sciences Science::Biological sciences::Biochemistry Science::Biological sciences::Molecular biology Bacteriology Pathogens The dynamic interaction of the N- and C-terminal domains of mycobacterial F-ATP synthase subunit ε is proposed to contribute to efficient coupling of H+-translocation and ATP synthesis. Here, we investigate crosstalk between both subunit ε domains by introducing chromosomal atpC missense mutations in the C-terminal helix 2 of ε predicted to disrupt inter domain and subunit ε-α crosstalk and therefore coupling. The ε mutant εR105A,R111A,R113A,R115A (ε4A) showed decreased intracellular ATP, slower growth rates and lower molar growth yields on non-fermentable carbon sources. Cellular respiration and metabolism were all accelerated in the mutant strain indicative of dysregulated oxidative phosphorylation. The ε4A mutant exhibited an altered colony morphology and was hypersusceptible to cell wall-acting antimicrobials suggesting defective cell wall biosynthesis. In silico screening identified a novel mycobacterial F-ATP synthase inhibitor disrupting ε’s coupling activity demonstrating the potential to advance this regulation as a new area for mycobacterial F-ATP synthase inhibitor development. NRF (Natl Research Foundation, S’pore) NMRC (Natl Medical Research Council, S’pore) MOH (Min. of Health, S’pore) Published version 2020-05-08T01:13:15Z 2020-05-08T01:13:15Z 2019 Journal Article Saw, W.-G., Wu, M.-L., Ragunathan, P., Biuković, G., Lau, A.-M., Shin, J., . . . Grüber, G. (2019). Disrupting coupling within mycobacterial F-ATP synthases subunit ε causes dysregulated energy production and cell wall biosynthesis. Scientific Reports, 9, 16759-. doi:10.1038/s41598-019-53107-3 2045-2322 https://hdl.handle.net/10356/138536 10.1038/s41598-019-53107-3 31727946 2-s2.0-85075033496 9 en Scientific Reports © 2019 The Author(s) (Nature Publishing Group). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. application/pdf |
| spellingShingle | Science::Biological sciences::Biochemistry Science::Biological sciences::Molecular biology Bacteriology Pathogens Saw, Wuan-Geok Wu, Mu-Lu Ragunathan, Priya Biuković, Goran Lau, Aik-Meng Shin, Joon Harikishore, Amaravadhi Cheung, Chen-Yi Hards, Kiel Sarathy, Jickky Palmae Bates, Roderick Wayland Cook, Gregory M. Dick, Thomas Grüber, Gerhard Disrupting coupling within mycobacterial F-ATP synthases subunit ε causes dysregulated energy production and cell wall biosynthesis |
| title | Disrupting coupling within mycobacterial F-ATP synthases subunit ε causes dysregulated energy production and cell wall biosynthesis |
| title_full | Disrupting coupling within mycobacterial F-ATP synthases subunit ε causes dysregulated energy production and cell wall biosynthesis |
| title_fullStr | Disrupting coupling within mycobacterial F-ATP synthases subunit ε causes dysregulated energy production and cell wall biosynthesis |
| title_full_unstemmed | Disrupting coupling within mycobacterial F-ATP synthases subunit ε causes dysregulated energy production and cell wall biosynthesis |
| title_short | Disrupting coupling within mycobacterial F-ATP synthases subunit ε causes dysregulated energy production and cell wall biosynthesis |
| title_sort | disrupting coupling within mycobacterial f atp synthases subunit ε causes dysregulated energy production and cell wall biosynthesis |
| topic | Science::Biological sciences::Biochemistry Science::Biological sciences::Molecular biology Bacteriology Pathogens |
| url | https://hdl.handle.net/10356/138536 |
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