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Structure of the essential inner membrane lipopolysaccharide-PbgA complex

Clairfeuille, Thomas ; Buchholz, Kerry R ; Li, Qingling ; Verschueren, Erik ; Liu, Peter ; Sangaraju, Dewakar ; Park, Summer ; Noland, Cameron L ; Storek, Kelly M ; Nickerson, Nicholas N ; Martin, Lynn ; Dela Vega, Trisha ; Miu, Anh ; Reeder, Janina ; Ruiz-Gonzalez, Maria ; Swem, Danielle ; Han, Guanghui ; DePonte, Daniel P ; Hunter, Mark S ; Gati, Cornelius ; Shahidi-Latham, Sheerin ; Xu, Min ; Skelton, Nicholas ; Sellers, Benjamin D ; Skippington, Elizabeth ; Sandoval, Wendy ; Hanan, Emily J ; Payandeh, Jian ; Rutherford, Steven T

Nature (London), 2020-08, Vol.584 (7821), p.479-483 [Periódico revisado por pares]

England: Nature Publishing Group

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Título:
Structure of the essential inner membrane lipopolysaccharide-PbgA complex
Autor: Clairfeuille, Thomas ; Buchholz, Kerry R ; Li, Qingling ; Verschueren, Erik ; Liu, Peter ; Sangaraju, Dewakar ; Park, Summer ; Noland, Cameron L ; Storek, Kelly M ; Nickerson, Nicholas N ; Martin, Lynn ; Dela Vega, Trisha ; Miu, Anh ; Reeder, Janina ; Ruiz-Gonzalez, Maria ; Swem, Danielle ; Han, Guanghui ; DePonte, Daniel P ; Hunter, Mark S ; Gati, Cornelius ; Shahidi-Latham, Sheerin ; Xu, Min ; Skelton, Nicholas ; Sellers, Benjamin D ; Skippington, Elizabeth ; Sandoval, Wendy ; Hanan, Emily J ; Payandeh, Jian ; Rutherford, Steven T
Assuntos: Amidohydrolases - chemistry ; Amidohydrolases - metabolism ; Amino Acid Motifs ; Analysis ; Antibiotics ; Bacteria ; Bacterial Outer Membrane - chemistry ; Bacterial Outer Membrane - metabolism ; BASIC BIOLOGICAL SCIENCES ; Binding Sites ; Biosynthesis ; Cardiolipin ; Cell division ; Cell Membrane - chemistry ; Cell Membrane - metabolism ; Cell membranes ; Control ; Depletion ; E coli ; Enzyme Stability ; Enzymes ; Escherichia coli ; Escherichia coli - chemistry ; Escherichia coli - cytology ; Escherichia coli - drug effects ; Escherichia coli - pathogenicity ; Escherichia coli Proteins - chemistry ; Escherichia coli Proteins - metabolism ; Experiments ; Genes, Essential ; Gram-negative bacteria ; Gram-positive bacteria ; Hydrolases - chemistry ; Hydrolases - metabolism ; Identification and classification ; Lipid A ; Lipid A - chemistry ; Lipid A - metabolism ; Lipids ; Lipopolysaccharides ; Lipopolysaccharides - biosynthesis ; Lipopolysaccharides - chemistry ; Lipopolysaccharides - metabolism ; Membrane proteins ; Membranes ; Microbial Sensitivity Tests ; Microbial Viability - drug effects ; microbiology ; Models, Molecular ; Multidrug resistance ; Mutation ; Pathogenesis ; Peptide Fragments - chemistry ; Peptide Fragments - metabolism ; Peptide Fragments - pharmacology ; Peptides ; Periplasm - chemistry ; Periplasm - metabolism ; Physiology ; Polymyxins ; Protein Binding ; Septic shock ; structural biology ; Structure ; Virulence
É parte de: Nature (London), 2020-08, Vol.584 (7821), p.479-483
Notas: AC02-76SF00515; P41GM103393
USDOE Office of Science (SC), Basic Energy Sciences (BES)
National Institutes of Health (NIH)
Descrição: Lipopolysaccharide (LPS) resides in the outer membrane of Gram-negative bacteria where it is responsible for barrier function . LPS can cause death as a result of septic shock, and its lipid A core is the target of polymyxin antibiotics . Despite the clinical importance of polymyxins and the emergence of multidrug resistant strains , 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 transporter , 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 enzyme . 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.
Editor: England: Nature Publishing Group
Idioma: Inglês

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Structure of the essential inner membrane lipopolysaccharide-PbgA complex

England: Nature Publishing Group

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