Structural basis of peptide secretion for Quorum sensing by ComA
Abstract Quorum sensing (QS) is a crucial regulatory mechanism controlling bacterial signalling and holds promise for novel therapies against antimicrobial resistance. In Gram-positive bacteria, such as Streptococcus pneumoniae, ComA is a conserved efflux pump responsible for the maturation and secr...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-42852-9 |
| _version_ | 1797630106438467584 |
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| author | Lin Yu Xin Xu Wan-Zhen Chua Hao Feng Zheng Ser Kai Shao Jian Shi Yumei Wang Zongli Li Radoslaw M. Sobota Lok-To Sham Min Luo |
| author_facet | Lin Yu Xin Xu Wan-Zhen Chua Hao Feng Zheng Ser Kai Shao Jian Shi Yumei Wang Zongli Li Radoslaw M. Sobota Lok-To Sham Min Luo |
| author_sort | Lin Yu |
| collection | DOAJ |
| description | Abstract Quorum sensing (QS) is a crucial regulatory mechanism controlling bacterial signalling and holds promise for novel therapies against antimicrobial resistance. In Gram-positive bacteria, such as Streptococcus pneumoniae, ComA is a conserved efflux pump responsible for the maturation and secretion of peptide signals, including the competence-stimulating peptide (CSP), yet its structure and function remain unclear. Here, we functionally characterize ComA as an ABC transporter with high ATP affinity and determined its cryo-EM structures in the presence or absence of CSP or nucleotides. Our findings reveal a network of strong electrostatic interactions unique to ComA at the intracellular gate, a putative binding pocket for two CSP molecules, and negatively charged residues facilitating CSP translocation. Mutations of these residues affect ComA’s peptidase activity in-vitro and prevent CSP export in-vivo. We demonstrate that ATP-Mg2+ triggers the outward-facing conformation of ComA for CSP release, rather than ATP alone. Our study provides molecular insights into the QS signal peptide secretion, highlighting potential targets for QS-targeting drugs. |
| first_indexed | 2024-03-11T11:03:18Z |
| format | Article |
| id | doaj.art-76991d3da0104c928b2ddac4f9dafee5 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-11T11:03:18Z |
| publishDate | 2023-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-76991d3da0104c928b2ddac4f9dafee52023-11-12T12:22:50ZengNature PortfolioNature Communications2041-17232023-11-0114111710.1038/s41467-023-42852-9Structural basis of peptide secretion for Quorum sensing by ComALin Yu0Xin Xu1Wan-Zhen Chua2Hao Feng3Zheng Ser4Kai Shao5Jian Shi6Yumei Wang7Zongli Li8Radoslaw M. Sobota9Lok-To Sham10Min Luo11Department of Biological Sciences, Faculty of Science, National University of SingaporeDepartment of Biological Sciences, Faculty of Science, National University of SingaporeInfectious Diseases Translational Research Programme and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of SingaporeDepartment of Biological Sciences, Faculty of Science, National University of SingaporeFunctional Proteomics Laboratory, SingMass National Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR)Department of Biological Sciences, Faculty of Science, National University of SingaporeDepartment of Biological Sciences, Faculty of Science, National University of SingaporeBeijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of ScienceHarvard Cryo-EM Center for Structural Biology, Harvard Medical SchoolFunctional Proteomics Laboratory, SingMass National Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR)Infectious Diseases Translational Research Programme and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of SingaporeDepartment of Biological Sciences, Faculty of Science, National University of SingaporeAbstract Quorum sensing (QS) is a crucial regulatory mechanism controlling bacterial signalling and holds promise for novel therapies against antimicrobial resistance. In Gram-positive bacteria, such as Streptococcus pneumoniae, ComA is a conserved efflux pump responsible for the maturation and secretion of peptide signals, including the competence-stimulating peptide (CSP), yet its structure and function remain unclear. Here, we functionally characterize ComA as an ABC transporter with high ATP affinity and determined its cryo-EM structures in the presence or absence of CSP or nucleotides. Our findings reveal a network of strong electrostatic interactions unique to ComA at the intracellular gate, a putative binding pocket for two CSP molecules, and negatively charged residues facilitating CSP translocation. Mutations of these residues affect ComA’s peptidase activity in-vitro and prevent CSP export in-vivo. We demonstrate that ATP-Mg2+ triggers the outward-facing conformation of ComA for CSP release, rather than ATP alone. Our study provides molecular insights into the QS signal peptide secretion, highlighting potential targets for QS-targeting drugs.https://doi.org/10.1038/s41467-023-42852-9 |
| spellingShingle | Lin Yu Xin Xu Wan-Zhen Chua Hao Feng Zheng Ser Kai Shao Jian Shi Yumei Wang Zongli Li Radoslaw M. Sobota Lok-To Sham Min Luo Structural basis of peptide secretion for Quorum sensing by ComA Nature Communications |
| title | Structural basis of peptide secretion for Quorum sensing by ComA |
| title_full | Structural basis of peptide secretion for Quorum sensing by ComA |
| title_fullStr | Structural basis of peptide secretion for Quorum sensing by ComA |
| title_full_unstemmed | Structural basis of peptide secretion for Quorum sensing by ComA |
| title_short | Structural basis of peptide secretion for Quorum sensing by ComA |
| title_sort | structural basis of peptide secretion for quorum sensing by coma |
| url | https://doi.org/10.1038/s41467-023-42852-9 |
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