Journal
ACS INFECTIOUS DISEASES
Volume 4, Issue 7, Pages 1146-1156Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.8b00094
Keywords
quorum sensing molecule (QSM); acyl homoserine lactone (ATIL); bitter taste receptor (T2R); G protein-coupled receptor (GPCR); structure-function
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Funding
- Cystic Fibrosis Canada operating grant [491120]
- Natural Sciences and Engineering Research Council of Canada [RGPIN-2014-04099]
- University of Manitoba
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The 25 bitter taste receptors (T2Rs) in humans are novel players in mediating host pathogen responses in the airways and innate immunity. The chemosensory T2Rs are expressed in different extraoral tissues and perform diverse pathophysiological roles from mediating bronchodilation to detecting bacterial infection in the airways. T2Rs were suggested to be activated by multiple bacterial quorum sensing molecules (QSMs). However, whether bacterial QSMs bind to T2Rs and the structural features on T2Rs has not yet been characterized. Here, we analyzed the taste sensory profiles of QSMs including acyl homoserine lactones (C4-AHL, C8-AHL, and 3-oxoC12-AHL) and hydroxyquinolones (HHQ and NHQ) predominantly secreted by Gram-negative bacteria and characterized the candidate T2Rs interacting with different QSMs using structure function approaches. The potency of the above QSMs for T2Rs significantly expressed in the airways, namely T2R4, T2R14, and T2R20, was characterized. 3-0xo-C12-AHL activated T2R4, T2R14, and T2R20, while C8-AHL activated T2R4 and T2R14 with strong potency. The T2R amino acid residues involved in the interactions were characterized by molecular-model-guided site-directed mutagenesis. AHLs bind to a similar orthosteric site present on the extracellular surface in all three T2Rs with significant contributions from residues in extracellular loop 2. Our results reveal the mode of binding of AHLs for different T2Rs and provide biochemical insights into their interactions. This study will facilitate mechanistic studies aimed at understanding the role of these T2Rs as sensors of bacteria and in host pathogen interactions.
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