Structural determinants driving homoserine lactone ligand selection in the LasR quorum-sensing receptor.

TitleStructural determinants driving homoserine lactone ligand selection in the LasR quorum-sensing receptor.
Publication TypeJournal Article
Year of Publication2019
AuthorsMcCready, AR, Paczkowski, JE, Henke, BR, Bassler, BL
JournalProc Natl Acad Sci U S A
Date Published2019 01 02
Keywords4-Butyrolactone, Bacterial Proteins, Blotting, Western, Ligands, Mutagenesis, Site-Directed, Protein Structure, Quaternary, Pseudomonas aeruginosa, Quorum Sensing, Structure-Activity Relationship, Trans-Activators

Quorum sensing is a cell-cell communication process that bacteria use to orchestrate group behaviors. Quorum sensing is mediated by signal molecules called autoinducers. Autoinducers are often structurally similar, raising questions concerning how bacteria distinguish among them. Here, we use the LasR quorum-sensing receptor to explore signal discrimination. The cognate autoinducer, 3OC homoserine lactone (3OCHSL), is a more potent activator of LasR than other homoserine lactones. However, other homoserine lactones can elicit LasR-dependent quorum-sensing responses, showing that LasR displays ligand promiscuity. We identify mutants that alter which homoserine lactones LasR detects. Substitution at residue S129 decreases the LasR response to 3OCHSL, while enhancing discrimination against noncognate autoinducers. Conversely, the LasR L130F mutation increases the potency of 3OCHSL and other homoserine lactones. We solve crystal structures of LasR ligand-binding domains complexed with noncognate autoinducers. Comparison with existing structures reveals that ligand selectivity/sensitivity is mediated by a flexible loop near the ligand-binding site. We show that LasR variants with modified ligand preferences exhibit altered quorum-sensing responses to autoinducers in vivo. We suggest that possessing some ligand promiscuity endows LasR with the ability to optimally regulate quorum-sensing traits.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID30559209
PubMed Central IDPMC6320529
Grant ListR01 GM065859 / GM / NIGMS NIH HHS / United States
R37 GM065859 / GM / NIGMS NIH HHS / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States
/ Howard Hughes Medical Institute / Howard Hughes Medical Institute / United States