@article{3860ad4a534649c38069ab56a1e6a907,
title = "A Canonical Biophysical Model of the CsrA Global Regulator Suggests Flexible Regulator-Target Interactions",
abstract = "Bacterial global post-transcriptional regulators execute hundreds of interactions with targets that display varying molecular features while retaining specificity. Herein, we develop, validate, and apply a biophysical, statistical thermodynamic model of canonical target mRNA interactions with the CsrA global post-transcriptional regulator to understand the molecular features that contribute to target regulation. Altogether, we model interactions of CsrA with a pool of 236 mRNA: 107 are experimentally regulated by CsrA and 129 are suspected interaction partners. Guided by current understanding of CsrA-mRNA interactions, we incorporate (i) mRNA nucleotide sequence, (ii) cooperativity of CsrA-mRNA binding, and (iii) minimization of mRNA structural changes to identify an ensemble of likely binding sites and their free energies. The regulatory impact of bound CsrA on mRNA translation is determined with the RBS calculator. Predicted regulation of 66 experimentally regulated mRNAs adheres to the principles of canonical CsrA-mRNA interactions; the remainder implies that other, diverse mechanisms may underlie CsrA-mRNA interaction and regulation. Importantly, results suggest that this global regulator may bind targets in multiple conformations, via flexible stretches of overlapping predicted binding sites. This novel observation expands the notion that CsrA always binds to its targets at specific consensus sequences.",
author = "Leistra, {A. N.} and G. Gelderman and Sowa, {S. W.} and A. Moon-Walker and Salis, {H. M.} and Contreras, {L. M.}",
note = "Funding Information: We also acknowledge the Welch Foundation (Grant F-1756 to L.M.C.), the Air Force Office of Scientific Research (Grant FA9550-16-1-0174 to L.M.C.) and the National Science Foundation (Grant MCB 1716777 to L.M.C. and DGE-1610403 to A.N.L.) for funding associated with the work at the University of Texas at Austin. For the work at Penn State University, we acknowledge and thank the following funding sources: Air Force Office of Scientific Research (Grant FA9550-14-1-0089 to H.M.S.), the Office of Naval Research (Grant N00014-13-1-0074 to H.M.S.), and an NSF Career Award (Grant CBET- 1253641 to H.M.S.). Funding Information: We wish to thank Jordan K. Villa and Mia K. Mihailovic for helpful readings of the manuscript and Nicholas Curtis for help with RNA structure predictions. We also acknowledge the Welch Foundation (Grant F-1756 to L.M.C.), the Air Force Office of Scientific Research (Grant FA9550-16-1-0174 to L.M.C.) and the National Science Foundation (Grant MCB 1716777 to L.M.C. and DGE-1610403 to A.N.L.) for funding associated with the work at the University of Texas at Austin. For the work at Penn State University, we acknowledge and thank the following funding sources: Air Force Office of Scientific Research (Grant FA9550-14-1-0089 to H.M.S.), the Office of Naval Research (Grant N00014-13-1-0074 to H.M.S.), and an NSF Career Award (Grant CBET-1253641 to H.M.S.). Additionally, S.S. thanks a Named Graduate Fellowship from the University of Texas at Austin and A.N.L. thanks the University of Texas at Austin Graduate School Provost and McKetta Department of Chemical Engineering Thrust fellowships for funding.",
year = "2018",
month = dec,
day = "1",
doi = "10.1038/s41598-018-27474-2",
language = "English (US)",
volume = "8",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",
}