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Structural determinants driving homoserine lactone ligand selection in the Pseudomonas aeruginosa LasR quorum-sensing receptor.
Proc Natl Acad Sci U S A. 2019 01 02; 116(1):245-254.PN

Abstract

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 Pseudomonas aeruginosa LasR quorum-sensing receptor to explore signal discrimination. The cognate autoinducer, 3OC12 homoserine lactone (3OC12HSL), 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 3OC12HSL, while enhancing discrimination against noncognate autoinducers. Conversely, the LasR L130F mutation increases the potency of 3OC12HSL 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.

Authors+Show Affiliations

Department of Molecular Biology, Princeton University, Princeton, NJ 08544.Department of Molecular Biology, Princeton University, Princeton, NJ 08544.Opti-Mol Consulting, LLC, Cary, NC 27513.Department of Molecular Biology, Princeton University, Princeton, NJ 08544; bbassler@princeton.edu. Howard Hughes Medical Institute, Chevy Chase, MD 20815.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

30559209

Citation

McCready, Amelia R., et al. "Structural Determinants Driving Homoserine Lactone Ligand Selection in the Pseudomonas Aeruginosa LasR Quorum-sensing Receptor." Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 1, 2019, pp. 245-254.
McCready AR, Paczkowski JE, Henke BR, et al. Structural determinants driving homoserine lactone ligand selection in the Pseudomonas aeruginosa LasR quorum-sensing receptor. Proc Natl Acad Sci USA. 2019;116(1):245-254.
McCready, A. R., Paczkowski, J. E., Henke, B. R., & Bassler, B. L. (2019). Structural determinants driving homoserine lactone ligand selection in the Pseudomonas aeruginosa LasR quorum-sensing receptor. Proceedings of the National Academy of Sciences of the United States of America, 116(1), 245-254. https://doi.org/10.1073/pnas.1817239116
McCready AR, et al. Structural Determinants Driving Homoserine Lactone Ligand Selection in the Pseudomonas Aeruginosa LasR Quorum-sensing Receptor. Proc Natl Acad Sci USA. 2019 01 2;116(1):245-254. PubMed PMID: 30559209.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structural determinants driving homoserine lactone ligand selection in the Pseudomonas aeruginosa LasR quorum-sensing receptor. AU - McCready,Amelia R, AU - Paczkowski,Jon E, AU - Henke,Brad R, AU - Bassler,Bonnie L, Y1 - 2018/12/17/ PY - 2018/12/19/pubmed PY - 2019/3/19/medline PY - 2018/12/19/entrez KW - LasR KW - Pseudomonas aeruginosa KW - crystal structure KW - homoserine lactone KW - quorum sensing SP - 245 EP - 254 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc. Natl. Acad. Sci. U.S.A. VL - 116 IS - 1 N2 - 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 Pseudomonas aeruginosa LasR quorum-sensing receptor to explore signal discrimination. The cognate autoinducer, 3OC12 homoserine lactone (3OC12HSL), 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 3OC12HSL, while enhancing discrimination against noncognate autoinducers. Conversely, the LasR L130F mutation increases the potency of 3OC12HSL 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. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/30559209/Structural_determinants_driving_homoserine_lactone_ligand_selection_in_the_Pseudomonas_aeruginosa_LasR_quorum_sensing_receptor_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=30559209 DB - PRIME DP - Unbound Medicine ER -