Thomas Clairfeuille, Kerry R. Buchholz, Qingling Li, Erik Verschueren, Peter Liu, Dewakar Sangaraju, Summer Park, Cameron L. Noland, Kelly M. Storek, Nicholas N. Nickerson, Lynn Martin, Trisha Dela Vega, Anh Miu, Janina Reeder, Maria Ruiz-Gonzalez, Danielle Swem, Guanghui Han, Daniel P. DePonte, Mark S. Hunter, Cornelius Gati, Sheerin Shahidi-Latham, Min Xu, Nicholas Skelton, Benjamin D. Sellers, Elizabeth Skippington, Wendy Sandoval, Emily J. Hanan, Jian Payandeh, Steven T. Rutherford
{"title":"重要内膜脂多糖-PbgA复合物的结构","authors":"Thomas Clairfeuille, Kerry R. Buchholz, Qingling Li, Erik Verschueren, Peter Liu, Dewakar Sangaraju, Summer Park, Cameron L. Noland, Kelly M. Storek, Nicholas N. Nickerson, Lynn Martin, Trisha Dela Vega, Anh Miu, Janina Reeder, Maria Ruiz-Gonzalez, Danielle Swem, Guanghui Han, Daniel P. DePonte, Mark S. Hunter, Cornelius Gati, Sheerin Shahidi-Latham, Min Xu, Nicholas Skelton, Benjamin D. Sellers, Elizabeth Skippington, Wendy Sandoval, Emily J. Hanan, Jian Payandeh, Steven T. Rutherford","doi":"10.1038/s41586-020-2597-x","DOIUrl":null,"url":null,"abstract":"Lipopolysaccharide (LPS) resides in the outer membrane of Gram-negative bacteria where it is responsible for barrier function1,2. LPS can cause death as a result of septic shock, and its lipid A core is the target of polymyxin antibiotics3,4. Despite the clinical importance of polymyxins and the emergence of multidrug resistant strains5, our understanding of the bacterial factors that regulate LPS biogenesis is incomplete. Here we characterize the inner membrane protein PbgA and report that its depletion attenuates the virulence of Escherichia coli by reducing levels of LPS and outer membrane integrity. In contrast to previous claims that PbgA functions as a cardiolipin transporter6–9, our structural analyses and physiological studies identify a lipid A-binding motif along the periplasmic leaflet of the inner membrane. Synthetic PbgA-derived peptides selectively bind to LPS in vitro and inhibit the growth of diverse Gram-negative bacteria, including polymyxin-resistant strains. Proteomic, genetic and pharmacological experiments uncover a model in which direct periplasmic sensing of LPS by PbgA coordinates the biosynthesis of lipid A by regulating the stability of LpxC, a key cytoplasmic biosynthetic enzyme10–12. In summary, we find that PbgA has an unexpected but essential role in the regulation of LPS biogenesis, presents a new structural basis for the selective recognition of lipids, and provides opportunities for future antibiotic discovery. Structural and physiological studies show that the inner membrane protein PbgA is a crucial sensor of lipopolysaccharide (LPS) and regulates the activity of the LPS biosynthesis enzyme LpxC.","PeriodicalId":18787,"journal":{"name":"Nature","volume":null,"pages":null},"PeriodicalIF":50.5000,"publicationDate":"2020-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41586-020-2597-x","citationCount":"54","resultStr":"{\"title\":\"Structure of the essential inner membrane lipopolysaccharide–PbgA complex\",\"authors\":\"Thomas Clairfeuille, Kerry R. Buchholz, Qingling Li, Erik Verschueren, Peter Liu, Dewakar Sangaraju, Summer Park, Cameron L. Noland, Kelly M. Storek, Nicholas N. Nickerson, Lynn Martin, Trisha Dela Vega, Anh Miu, Janina Reeder, Maria Ruiz-Gonzalez, Danielle Swem, Guanghui Han, Daniel P. DePonte, Mark S. Hunter, Cornelius Gati, Sheerin Shahidi-Latham, Min Xu, Nicholas Skelton, Benjamin D. Sellers, Elizabeth Skippington, Wendy Sandoval, Emily J. Hanan, Jian Payandeh, Steven T. Rutherford\",\"doi\":\"10.1038/s41586-020-2597-x\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Lipopolysaccharide (LPS) resides in the outer membrane of Gram-negative bacteria where it is responsible for barrier function1,2. LPS can cause death as a result of septic shock, and its lipid A core is the target of polymyxin antibiotics3,4. Despite the clinical importance of polymyxins and the emergence of multidrug resistant strains5, our understanding of the bacterial factors that regulate LPS biogenesis is incomplete. Here we characterize the inner membrane protein PbgA and report that its depletion attenuates the virulence of Escherichia coli by reducing levels of LPS and outer membrane integrity. In contrast to previous claims that PbgA functions as a cardiolipin transporter6–9, our structural analyses and physiological studies identify a lipid A-binding motif along the periplasmic leaflet of the inner membrane. Synthetic PbgA-derived peptides selectively bind to LPS in vitro and inhibit the growth of diverse Gram-negative bacteria, including polymyxin-resistant strains. Proteomic, genetic and pharmacological experiments uncover a model in which direct periplasmic sensing of LPS by PbgA coordinates the biosynthesis of lipid A by regulating the stability of LpxC, a key cytoplasmic biosynthetic enzyme10–12. In summary, we find that PbgA has an unexpected but essential role in the regulation of LPS biogenesis, presents a new structural basis for the selective recognition of lipids, and provides opportunities for future antibiotic discovery. Structural and physiological studies show that the inner membrane protein PbgA is a crucial sensor of lipopolysaccharide (LPS) and regulates the activity of the LPS biosynthesis enzyme LpxC.\",\"PeriodicalId\":18787,\"journal\":{\"name\":\"Nature\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":50.5000,\"publicationDate\":\"2020-08-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1038/s41586-020-2597-x\",\"citationCount\":\"54\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nature\",\"FirstCategoryId\":\"103\",\"ListUrlMain\":\"https://www.nature.com/articles/s41586-020-2597-x\",\"RegionNum\":1,\"RegionCategory\":\"综合性期刊\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MULTIDISCIPLINARY SCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature","FirstCategoryId":"103","ListUrlMain":"https://www.nature.com/articles/s41586-020-2597-x","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
Structure of the essential inner membrane lipopolysaccharide–PbgA complex
Lipopolysaccharide (LPS) resides in the outer membrane of Gram-negative bacteria where it is responsible for barrier function1,2. LPS can cause death as a result of septic shock, and its lipid A core is the target of polymyxin antibiotics3,4. Despite the clinical importance of polymyxins and the emergence of multidrug resistant strains5, our understanding of the bacterial factors that regulate LPS biogenesis is incomplete. Here we characterize the inner membrane protein PbgA and report that its depletion attenuates the virulence of Escherichia coli by reducing levels of LPS and outer membrane integrity. In contrast to previous claims that PbgA functions as a cardiolipin transporter6–9, our structural analyses and physiological studies identify a lipid A-binding motif along the periplasmic leaflet of the inner membrane. Synthetic PbgA-derived peptides selectively bind to LPS in vitro and inhibit the growth of diverse Gram-negative bacteria, including polymyxin-resistant strains. Proteomic, genetic and pharmacological experiments uncover a model in which direct periplasmic sensing of LPS by PbgA coordinates the biosynthesis of lipid A by regulating the stability of LpxC, a key cytoplasmic biosynthetic enzyme10–12. In summary, we find that PbgA has an unexpected but essential role in the regulation of LPS biogenesis, presents a new structural basis for the selective recognition of lipids, and provides opportunities for future antibiotic discovery. Structural and physiological studies show that the inner membrane protein PbgA is a crucial sensor of lipopolysaccharide (LPS) and regulates the activity of the LPS biosynthesis enzyme LpxC.
期刊介绍:
Nature is a prestigious international journal that publishes peer-reviewed research in various scientific and technological fields. The selection of articles is based on criteria such as originality, importance, interdisciplinary relevance, timeliness, accessibility, elegance, and surprising conclusions. In addition to showcasing significant scientific advances, Nature delivers rapid, authoritative, insightful news, and interpretation of current and upcoming trends impacting science, scientists, and the broader public. The journal serves a dual purpose: firstly, to promptly share noteworthy scientific advances and foster discussions among scientists, and secondly, to ensure the swift dissemination of scientific results globally, emphasizing their significance for knowledge, culture, and daily life.