An Adaptive Mutation in Enterococcus faecium LiaR Associated with Antimicrobial Peptide Resistance Mimics Phosphorylation and Stabilizes LiaR in an Activated State

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dc.citation.firstpage4503en_US
dc.citation.issueNumber22en_US
dc.citation.journalTitleJournal of Molecular Biologyen_US
dc.citation.lastpage4519en_US
dc.citation.volumeNumber428en_US
dc.contributor.authorDavlieva, Milyaen_US
dc.contributor.authorTovar-Yanez, Angelen_US
dc.contributor.authorDeBruler, Kimberlyen_US
dc.contributor.authorLeonard, Paul G.en_US
dc.contributor.authorZianni, Michael R.en_US
dc.contributor.authorArias, Cesar A.en_US
dc.contributor.authorShamoo, Yousifen_US
dc.date.accessioned2017-11-15T14:12:54Zen_US
dc.date.available2017-11-15T14:12:54Zen_US
dc.date.issued2016en_US
dc.description.abstractThe cyclic antimicrobial lipopeptide daptomycin (DAP) triggers the LiaFSR membrane stress response pathway in enterococci and many other Gram-positive organisms. LiaR is the response regulator that, upon phosphorylation, binds in a sequence-specific manner to DNA to regulate transcription in response to membrane stress. In clinical settings, non-susceptibility to DAP by Enterococcus faecium is correlated frequently with a mutation in LiaR of Trp73 to Cys (LiaRW73C). We have determined the structure of the activated E. faecium LiaR protein at 3.2 Å resolution and, in combination with solution studies, show that the activation of LiaR induces the formation of a LiaR dimer that increases LiaR affinity at least 40-fold for the extended regulatory regions upstream of the liaFSR and liaXYZ operons. In vitro, LiaRW73C induces phosphorylation-independent dimerization of LiaR and provides a biochemical basis for non-susceptibility to DAP by the upregulation of the LiaFSR regulon. A comparison of the E. faecalis LiaR, E. faecium LiaR, and the LiaR homolog from Staphylococcus aureus (VraR) and the mutations associated with DAP resistance suggests that physicochemical properties such as oligomerization state and DNA specificity, although tuned to the biology of each organism, share some features that could be targeted for new antimicrobials.en_US
dc.identifier.citationDavlieva, Milya, Tovar-Yanez, Angel, DeBruler, Kimberly, et al.. "An Adaptive Mutation in Enterococcus faecium LiaR Associated with Antimicrobial Peptide Resistance Mimics Phosphorylation and Stabilizes LiaR in an Activated State." <i>Journal of Molecular Biology,</i> 428, no. 22 (2016) Elsevier: 4503-4519. https://doi.org/10.1016/j.jmb.2016.09.016.en_US
dc.identifier.digitalnihms-818866en_US
dc.identifier.doihttps://doi.org/10.1016/j.jmb.2016.09.016en_US
dc.identifier.urihttps://hdl.handle.net/1911/98830en_US
dc.language.isoengen_US
dc.publisherElsevieren_US
dc.rightsThis is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by Elsevier.en_US
dc.subject.keywordE. faeciumen_US
dc.subject.keywordLiaRen_US
dc.subject.keywordX-rayen_US
dc.subject.keyworddaptomycin resistanceen_US
dc.subject.keywordresponse regulatoren_US
dc.titleAn Adaptive Mutation in Enterococcus faecium LiaR Associated with Antimicrobial Peptide Resistance Mimics Phosphorylation and Stabilizes LiaR in an Activated Stateen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpost-printen_US
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