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首页> 外文期刊>Journal of Molecular Biology >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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An Adaptive Mutation in Enterococcus faecium LiaR Associated with Antimicrobial Peptide Resistance Mimics Phosphorylation and Stabilizes LiaR in an Activated State

机译：粪肠球菌LiaR的自适应突变与抗菌肽耐药相关，可以模拟磷酸化并稳定激活状态下的LiaR。

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The 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 (LiaR(W73C)). We have determined the structure of the activated E. faecium LiaR protein at 3.2 A 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, LiaR(W73C) 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. (C) 2016 Elsevier Ltd. All rights reserved.
机译：环状抗菌脂肽达托霉素（DAP）触发肠球菌和许多其他革兰氏阳性生物体中的LiaFSR膜应激反应途径。 LiaR是一种响应调节剂，在磷酸化后会以序列特异性的方式与DNA结合，以响应膜应力调节转录。在临床环境中，粪肠球菌对DAP的不敏感性经常与Trp73的LiaR突变为Cys（LiaR（W73C））相关。我们已经确定了在3.2 A分辨率下激活的屎肠球菌LiaR蛋白的结构，并与溶液研究相结合，显示LiaR的激活诱导了LiaR二聚体的形成，该LiaR二聚体增加了LiaR亲和力至少40倍。 liaFSR和liaXYZ操纵子上游的调控区。在体外，LiaR（W73C）诱导LiaR的磷酸化非依赖性二聚化，并通过上调LiaFSR调节剂为DAP不敏感提供了生化基础。粪肠球菌LiaR，粪肠球菌LiaR和金黄色葡萄球菌（VraR）的LiaR同源物以及与DAP抗性相关的突变的比较表明，尽管已针对每种生物学进行了微调，但其理化性质如寡聚化状态和DNA特异性。生物体，具有一些可能针对新抗菌药的功能。 （C）2016 Elsevier Ltd.保留所有权利。

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