A covariation analysis reveals elements of selectivity in quorum sensing systems

Abstract

Many bacteria communicate with kin and coordinate group behaviors through a form of cell-cell signaling called acyl-homoserine lactone (AHL) quorum sensing (QS). In these systems, a signal synthase produces an AHL to which its paired receptor selectively responds. Selectivity is fundamental to cell signaling. Despite its importance, it has been challenging to determine how this selectivity is achieved and how AHL QS systems evolve and diversify. We hypothesized that we could use covariation within the protein sequences of AHL synthases and receptors to identify selectivity residues. We began by identifying about 6,000 unique synthase-receptor pairs. We then used the protein sequences of these pairs to identify covariation patterns and mapped the patterns onto the LasI/R system from Pseudomonas aeruginosa PAO1. The covarying residues in both proteins cluster around the ligand-binding sites. We demonstrate that these residues are involved in system selectivity toward the cognate signal and go on to engineer the Las system to both produce and respond to an alternate AHL signal. We have thus demonstrated that covariation methods provide a powerful approach for investigating selectivity in protein-small molecule interactions and have deepened our understanding of how communication systems evolve and diversify.

Molecular Mechanisms and Applications of N-Acyl Homoserine Lactone-Mediated Quorum Sensing in Bacteria

“…The production and diversity of AHL molecules are governed by the AHL synthase enzyme [ 38 , 39 ]. The genome sequencing of diverse bacteria indicated the existence of numerous AHL synthesis protein biomolecules in a bacterial population [ 40 , 41 , 42 ]. Bioassay detection approaches have also proven the presence of AHL molecules in bacterial culture extracts [ 43 , 44 ].…”

Bacteria‐Responsive Multidrug Delivery Nanosystem for Combating Long‐Term Biofilm‐Associated Infections

“…The inhibition of QS signaling regulates a variety of phenotypes, including the production of virulence factors in PAO1 [ 7b,34 ] and MRSA. [ 13 ] Elastase, a multifunctional metalloenzyme secreted by PAO1, is encoded by the lasB gene.…”

Cell-Cell Signaling Proteobacterial LuxR Solos: a Treasure Trove of Subgroups Having Different Origins, Ligands, and Ecological Roles

“…Only very few examples exist where the luxI -family gene is genetically unlinked from the cognate luxR -family gene ( 5 ). The luxI / R pairs likely shared a common origin coevolving as regulatory cassettes as reported by studies implementing statistical methods and covariation within their sequences ( 9 ). Many bacterial strains contain multiple luxI / luxR homologues acquired from an independent source via horizontal gene transfer ( 5 , 10 , 11 ).…”