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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.

The pathogen recognition receptors NOD1/2 recognize bacterial cell wall components and signal through their downstream adapter kinase RIP2 via a CARD (Caspase activation and recruitment domain) mediated oligomerization process. Here the authors present the cryo-EM structure of the active RIP2-CARD filament and discuss implications for NOD1/2-RIP2 signalling.

Members of the transient receptor potential (TRP) ion channels conduct cations into cells upon activation by a variety of signals. Here authors present the cryo-EM structure of TRPC4 in its unliganded (apo) state, which provides molecular insights into TRPC4's ion selectivity and TPR channel evolution.