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Proc Natl Acad Sci U S A

Title:		Structure-function studies of Rgg binding to pheromones and target promoters reveal a model of transcription factor interplay
Author(s):		Capodagli GC; Tylor KM; Kaelber JT; Petrou VI; Federle MJ; Neiditch MB;
Address:		"Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers Biomedical Health Sciences, Newark, NJ 07103. Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60607. Rutgers New Jersey Cryo-Electron Microscopy & Tomography Core Facility, Rutgers University, Piscataway, NJ 08854. Institute for Quantitative Biomedicine, Rutgers University, Piscataway, NJ 08854. Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers Biomedical Health Sciences, Newark, NJ 07103; vasileios.petrou@rutgers.edu mfederle@uic.edu matthew.neiditch@rutgers.edu. Center for Immunity and Inflammation, New Jersey Medical School, Rutgers Biomedical Health Sciences, Newark, NJ 07103. Department of Pharamaceutical Sciences, Center for Biomolecular Sciences, University of Illinois at Chicago, Chicago, IL 60607 vasileios.petrou@rutgers.edu mfederle@uic.edu matthew.neiditch@rutgers.edu"
Journal Title:		Proc Natl Acad Sci U S A
Year:		2020
Volume:		20200909
Issue:		39
Page Number:		24494 - 24502
DOI:		10.1073/pnas.2008427117
ISSN/ISBN:		1091-6490 (Electronic) 0027-8424 (Print) 0027-8424 (Linking)
Abstract:		"Regulator gene of glucosyltransferase (Rgg) family proteins, such as Rgg2 and Rgg3, have emerged as primary quorum-sensing regulated transcription factors in Streptococcus species, controlling virulence, antimicrobial resistance, and biofilm formation. Rgg2 and Rgg3 function is regulated by their interaction with oligopeptide quorum-sensing signals called short hydrophobic peptides (SHPs). The molecular basis of Rgg-SHP and Rgg-target DNA promoter specificity was unknown. To close this gap, we determined the cryoelectron microscopy (cryo-EM) structure of Streptococcus thermophilus Rgg3 bound to its quorum-sensing signal, SHP3, and the X-ray crystal structure of Rgg3 alone. Comparison of these structures with that of an Rgg in complex with cyclosporin A (CsA), an inhibitor of SHP-induced Rgg activity, reveals the molecular basis of CsA function. Furthermore, to determine how Rgg proteins recognize DNA promoters, we determined X-ray crystal structures of both Streptococcus dysgalactiae Rgg2 and S. thermophilus Rgg3 in complex with their target DNA promoters. The physiological importance of observed Rgg-DNA interactions was dissected using in vivo genetic experiments and in vitro biochemical assays. Based on these structure-function studies, we present a revised unifying model of Rgg regulatory interplay. In contrast to existing models, where Rgg2 proteins are transcriptional activators and Rgg3 proteins are transcriptional repressors, we propose that both are capable of transcriptional activation. However, when Rgg proteins with different activation requirements compete for the same DNA promoters, those with more stringent activation requirements function as repressors by blocking promoter access of SHP-bound conformationally active Rgg proteins. While a similar gene expression regulatory scenario has not been previously described, in all likelihood it is not unique to streptococci"
Keywords:		"Bacterial Proteins/*chemistry/genetics/*metabolism Cryoelectron Microscopy Gene Expression Regulation, Bacterial Pheromones/chemistry/*metabolism Streptococcus/genetics/metabolism Streptococcus thermophilus/chemistry/genetics/*metabolism Trans-Activators/;"
Notes:		"MedlineCapodagli, Glenn C Tylor, Kaitlyn M Kaelber, Jason T Petrou, Vasileios I Federle, Michael J Neiditch, Matthew B eng P41 GM103393/GM/NIGMS NIH HHS/ R00 GM123228/GM/NIGMS NIH HHS/ R01 AI091779/AI/NIAID NIH HHS/ R01 AI125452/AI/NIAID NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. 2020/09/11 Proc Natl Acad Sci U S A. 2020 Sep 29; 117(39):24494-24502. doi: 10.1073/pnas.2008427117. Epub 2020 Sep 9"