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.firstpage4503
dc.citation.issueNumber22
dc.citation.journalTitleJournal of Molecular Biology
dc.citation.lastpage4519
dc.citation.volumeNumber428
dc.contributor.authorDavlieva, Milya
dc.contributor.authorTovar-Yanez, Angel
dc.contributor.authorDeBruler, Kimberly
dc.contributor.authorLeonard, Paul G.
dc.contributor.authorZianni, Michael R.
dc.contributor.authorArias, Cesar A.
dc.contributor.authorShamoo, Yousif
dc.date.accessioned2017-11-15T14:12:54Z
dc.date.available2017-11-15T14:12:54Z
dc.date.issued2016
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.
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.
dc.identifier.digitalnihms-818866
dc.identifier.doihttps://doi.org/10.1016/j.jmb.2016.09.016
dc.identifier.urihttps://hdl.handle.net/1911/98830
dc.language.isoeng
dc.publisherElsevier
dc.rightsThis is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by Elsevier.
dc.subject.keywordE. faecium
dc.subject.keywordLiaR
dc.subject.keywordX-ray
dc.subject.keyworddaptomycin resistance
dc.subject.keywordresponse regulator
dc.titleAn Adaptive Mutation in Enterococcus faecium LiaR Associated with Antimicrobial Peptide Resistance Mimics Phosphorylation and Stabilizes LiaR in an Activated State
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpost-print
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