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Lipopolysaccharide Transport and Assembly at the Outer Membrane: the PEZ Model

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Lipopolysaccharide Transport and Assembly at the Outer Membrane: the PEZ Model REVIEWS Lipopolysaccharide transport and assembly at the outer membrane: the PEZ model Suguru Okuda1,2, David J. Sherman1, Thomas J. Silhavy3, Natividad Ruiz4 and Daniel Kahne1,5,6 Abstract | Gram-negative bacteria have a double-membrane cellular envelope that enables them to colonize harsh environments and prevents the entry of many clinically available antibiotics. A main component of most outer membranes is lipopolysaccharide (LPS), a glycolipid containing several fatty acyl chains and up to hundreds of sugars that is synthesized in the cytoplasm. In the past two decades, the proteins that are responsible for transporting LPS across the cellular envelope and assembling it at the cell surface in Escherichia coli have been identified, but it remains unclear how they function. In this Review, we discuss recent advances in this area and present a model that explains how energy from the cytoplasm is used to power LPS transport across the cellular envelope to the cell surface. Gram-negative bacteria have an inner membrane (IM), phosphate groups that mediate interactions with divalent which surrounds the cytoplasm, and an outer mem- metal ions (for example, Mg2+), which enables LPS mol- brane (OM), which is exposed to the environment. The ecules to pack tightly. The assembled LPS structure cre- OM of Gram-negative bacteria is essential, and its cor- ates a highly ordered network of sugar chains on the cell rect assembly is required for bacterial survival in harsh surface that makes the partitioning of hydrophobic mol- environments1. The OM is also the first point of contact ecules into this well-packed material unfavourable. The 1 Department of Chemistry and with the environment that surrounds the bacterial cell, hydrophobicity of LPS is directly responsible for why the Chemical Biology, Harvard University, Cambridge, and subtle changes to this membrane affect funda- development of new antibiotics to treat infections with Massachusetts 02138, USA. mental bacterial processes, such as motility, attachment Gram-negative bacteria has been so difficult, as many 2Department of Bio-system and pathogenesis2–6. drugs are relatively hydrophobic. Pharmacology, Graduate Similar to most membranes, the hydrophobic nature Although the composition and structure of the OM School of Medicine, Osaka University, of the lipidic bilayer of the OM prevents the passage of prevents the access of antibiotics and other molecules Osaka 565–0871, Japan. large polar molecules through electrostatic repulsion. to the cytoplasm, this barrier also presents challenges 3Department of However, the OM of many Gram-negative bacteria also for the transport of bacterial components that are pro- Molecular Biology, Princeton prevents small hydrophobic molecules from entering the duced inside the cell. For example, LPS molecules are University, Princeton, cell1. This unusual barrier function of the OM is a conse- synthesized in the cytoplasm, and the transport of these New Jersey 08544, USA. 4Department of Microbiology, quence of its structure. In most Gram-negative bacteria, large amphipathic molecules that contain many fatty The Ohio State University, the OM is an asymmetric lipid bilayer with lipopoly- acyl chains and hundreds of sugars across the IM, the Columbus, Ohio 43210, USA. saccharide (LPS) in the outer leaflet and phospho lipids periplasm and the OM, poses major challenges. Indeed, 5Department of Molecular and in the inner leaflet7–9 (FIG. 1). Although LPS is present in for more than a decade, the major question in the field Cellular Biology, Harvard University, Cambridge, most Gram-negative bacteria, bacterial cell surfaces of LPS biogenesis was what proteins are responsible for Massachusetts 02138, USA. have a great deal of structural diversity and LPS is not the transport of LPS across the cellular envelope and the 6Department of Biological produced by some bacteria that have an OM, such as assembly of LPS at the cell surface. Several of these LPS Chemistry and Molecular Borrelia burgdorferi, the causative agent of Lyme disease. transport (Lpt) proteins have since been identified, and Pharmacology, Harvard The diversity in cellular envelopes exemplifies how bac- the history of their identification using multidiscipli- Medical School, Boston, Massachusetts 02115, USA. teria have evolved to meet unique challenges in different nary approaches has been comprehensively discussed 10 Correspondence to D.K. environments and to adapt to new external pressures . (see REF. 11). However, although we now think that we [email protected] LPS is an amphipathic molecule that contains fatty know the essential players that are involved in the trans- doi:10.1038/nrmicro.2016.25 acyl chains attached to a polysaccharide containing port and assembly of LPS at the OM, detailed informa- Published online 30 Mar 2016 up to 200 sugars6 (FIG. 1). Some of these sugars contain tion about the function of these proteins is still lacking. NATURE REVIEWS | MICROBIOLOGY VOLUME 14 | JUNE 2016 | 337 ©2016 Mac millan Publishers Li mited. All ri ghts reserved. REVIEWS O-antigen repeat Hep Glc LptDE LPS Glc Outer core Gal Glc Outer membrane D Phospholipids P Hep Hep E PEtN P Hep Inner core Kdo Kdo Peptidoglycan O O A P O HO O O O– O O HO O NH O O O O NH LptB2FGC O P O O Periplasm – OH C O O HO O MsbA O HO F G Inner membrane Lipid A B B Cytoplasm ATP ADP+P LPS i ATP ADP+Pi Figure 1 | LPS transport pathway in Escherichia coli. Lipopolysaccharide (LPS) is synthesized on the cytoplasmic side Nature Reviews | Microbiology Periplasm of the inner membrane (IM) and flipped to the periplasmic side by the ATP-binding cassette (ABC) transporter MsbA. LPS An aqueous, densely is then transported to the cell surface by the LPS transport (Lpt) pathway. This pathway consists of seven essential proteins, packed compartment LptA, LptB, LptC, LptD, LptE, LptF and LptG. LPS is extracted from the IM in an ATP-dependent manner by the ABC between the Gram-negative transporter LptB2FG and transferred to LptC, which forms a complex with LptB2FG. LptC consists of a single membrane- inner membrane and outer spanning domain and a large periplasmic domain, which forms a periplasmic bridge with the soluble protein LptA and membrane. The periplasm the amino-terminal region of LptD. LPS transverses the aqueous periplasmic space through this protein bridge has a unique assortment of and reaches the cell surface with the aid of the carboxy-terminal domain of LptD, which forms a β‑barrel structure proteins and also contains a that is plugged by the outer membrane (OM) lipoprotein LptE. LPS is composed of lipid A, the inner and outer core thin layer of peptidoglycan. oligosaccharides, and the O antigen, which is highly variable and absent in Escherichia coli K-12. The letters A–G in the Lipid A figure correspond to the respective Lpt protein in the transport pathway. EtN, ethanolamine; Gal, d-galactose; Glc, The hydrophobic d-glucose; Hep, l-glycero-d-manno-heptose; Kdo, 3-deoxy-d-manno-octulosonic acid; P, phosphate; Pi, inorganic phosphate. glucosamine-based phospholipid anchor of lipopolysaccharide Therefore, over the past several years, biochemical, genetic Gram-negative organisms, is ligated to the lipid A–core molecules. Lipid A is also and structural studies have focused on how indivi dual Lpt oligosaccharide complex by an O antigen ligase, WaaL, known as endotoxin. components function and how they interact with each following its independent synthesis in the cytoplasm other. In addition, several intermediates of LPS transport and transport to the periplasm20–23. How LPS is sub- O antigen Attached to the core have been observed in vivo and in vitro. In this Review, sequently transported to, and assembled on, the cell oligosaccharide, this repetitive we summarize the current understanding of LPS trans- surface is much less understood. glycan is the outermost part of port and assembly at the OM, and discuss how recent In Escherichia coli, seven essential proteins, LptA (for- the lipopolysaccharide studies have established the function of the Lpt machin- merly known as YhbN), LptB (formerly known as YhbG), molecule and is a target of the host immune system. ery in directly facilitating the release of LPS from the LptC (formerly known as YrbK), LptD (formerly known IM and its transit across the peri plasmic compartment. as Imp/OstA), LptE (formerly known as RlpB), LptF ATP-binding cassette Furthermore, we propose a model that explains how (formerly known as YjgP) and LptG (formerly known transporter energy from the cytoplasm powers LPS transport to the as YjgQ), are required for the transport of LPS from the (ABC transporter). cell surface and highlight the most important questions outer leaflet of the IM to the outer leaflet of the OM11,24–26 A transmembrane protein (FIG. 1) complex that uses the energy in LPS transport and assembly that remain unanswered. Notably, all seven Lpt proteins are required, as derived from ATP binding and the depletion of individual Lpt components results hydrolysis to transport various LPS biogenesis in the accumulation of LPS on the periplasmic surface of substrates. These proteins are 27,28 The biosynthesis of LPS requires more than 100 genes the IM . An ABC transporter, LptB2FG, in association members of one of the largest bitopic membrane protein protein superfamilies and and much is known about the molecular mechanisms with a , LptC, is thought to extract 12–14 consist of transmembrane of the biosynthetic enzymes . LPS is composed of a LPS from the IM. The soluble protein LptA mediates the domains and conserved lipid A moiety, inner and outer core oligosaccharides, transit of LPS across the aqueous periplasmic compart- nucleotide-binding domains. and the O antigen6,13 (FIG. 1). The lipid A–core oligo- ment. Finally, the β-barrel membrane protein LptD and saccharide complex is synthesized on the cytoplasmic the OM lipoprotein LptE form a heterodimeric translocon Bitopic membrane protein A type of membrane protein side of the IM and flipped to the periplasmic side by in the OM that receives LPS from LptA and transports it that contains only one an ATP-binding cassette transporter (ABC transporter), to the cell surface, presumably without allowing LPS to transmembrane helix.
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