title: Lipopolysaccharide is inserted into the outer membrane through an intramembrane hole, a lumen gate, and the lateral opening of LptD.
abstract: Lipopolysaccharide (LPS) is essential for the vitality of most Gram-negative bacteria and plays an important role in bacterial multidrug resistance. The LptD/E translocon inserts LPS into the outer leaflet, the mechanism of which is poorly understood. Here, we report mutagenesis, functional assays, and molecular dynamics simulations of the LptD/E complex, which suggest two distinct pathways for the insertion of LPS. The N-terminal domain of LptD comprises a hydrophobic slide that injects the acyl tails of LPS directly into the outer membrane through an intramembrane hole, while the core oligosaccharide and O-antigen pass a lumen gate that triggers the unzipping of the lateral opening between strands β1C and β26C of the barrel of LptD, to finalize LPS insertion. Mutation of the LPS transport related residues or block of the LPS transport pathways results in the deaths of Escherichia coli. These findings are important for the development of novel antibiotics.
authors: Biomedical Research Centre, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK.
authors: Yinghong
authors: Y
authors: Gu
authors: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors: Phillip J
authors: PJ
authors: Stansfeld
authors: Biomedical Research Centre, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK.
authors: Yi
authors: Y
authors: Zeng
authors: Biomedical Sciences Research Complex, School of Chemistry, University of St Andrews, North Haugh, St Andrews KY16 9ST, UK.
authors: Haohao
authors: H
authors: Dong
authors: Laboratory of Department of Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, Guangdong 510080, China. Electronic address: wenjian166@gmail.com.
authors: Wenjian
authors: W
authors: Wang
authors: Biomedical Research Centre, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK. Electronic address: c.dong@uea.ac.uk.
authors: Changjiang
authors: C
authors: Dong
mesh_terms: D001425:Bacterial Outer Membrane Proteins / Q000737:chemistry*; D001665:Binding Sites; D001692:Biological Transport; D057927:Hydrophobic and Hydrophilic Interactions; D008070:Lipopolysaccharides / Q000737:chemistry*; D008958:Models, Molecular; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012486:Salmonella typhimurium / Q000737:chemistry*
chemical_list: D001425:Bacterial Outer Membrane Proteins; D008070:Lipopolysaccharides