Structural basis of peptide secretion for Quorum sensing by ComA

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 () and Min Luo ()
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Lin Yu: National University of Singapore
Xin Xu: National University of Singapore
Wan-Zhen Chua: National University of Singapore
Hao Feng: National University of Singapore
Zheng Ser: Technology and Research (A*STAR)
Kai Shao: National University of Singapore
Jian Shi: National University of Singapore
Yumei Wang: Chinese Academy of Science
Zongli Li: Harvard Medical School
Radoslaw M. Sobota: Technology and Research (A*STAR)
Lok-To Sham: National University of Singapore
Min Luo: National University of Singapore

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42852-9

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