Nature Communications (Nov 2023)

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,
  • Min Luo

DOI
https://doi.org/10.1038/s41467-023-42852-9
Journal volume & issue
Vol. 14, no. 1
pp. 1 – 17

Abstract

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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.