The Crystal Structure of Lipopolysaccharide Binding Protein Reveals the Location of a Frequent Mutation that Impairs Innate Immunity

Eckert, Jana; Kim, Young Jin; Kim, Jung I.; Gürtler, Kathleen; Oh, Djin-Ye; Sur, Saubashya; Lundvall, Linn; Hamann, Lutz; Ploeg, A. van der; Pickkers, Peter; Giamarellos‐Bourboulis, Evangelos J.; Kubarenko, Andriy V.; Weber, Alexander N.R.; Kabesch, Michael; Kumpf, Oliver; An, Hyun‐Jung; Lee, Jie‐Oh; Schumann, Ralf R.

doi:10.1016/j.immuni.2013.09.005

Cited by 95 publications

(94 citation statements)

References 51 publications

(50 reference statements)

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“…These authors point to the fact that the FhuA LPS-binding motif bears significant resemblance to eukaryotic LPS-binding proteins. We think it is noteworthy that many of these proteins, in particular LALF, bactericidal permeability increasing protein (BPI) (41), and LPS-binding protein (LBP) (42), possess functions that extend beyond the mere binding of LPS. It has been hypothesized that the eukaryotic structural homolog LALF participates in not only the binding of LPS but also in its transport to and insertion into phospholipids membranes as part of the Limulus host immune response (23,35).…”

Section: Discussionmentioning

confidence: 99%

LptE binds to and alters the physical state of LPS to catalyze its assembly at the cell surface

Malojcic

Andres

Grabowicz

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The assembly of lipopolysaccharide (LPS) on the surface of Gramnegative bacterial cells is essential for their viability and is achieved by the seven-protein LPS transport (Lpt) pathway. The outer membrane (OM) lipoprotein LptE and the β-barrel membrane protein LptD form a complex that assembles LPS into the outer leaflet of the OM. We report a crystal structure of the Escherichia coli OM lipoprotein LptE at 2.34 Å. The structure reveals homology to eukaryotic LPS-binding proteins and allowed for the prediction of an LPS-binding site, which was confirmed by genetic and biophysical experiments. Specific point mutations at this site lead to defects in OM biogenesis. We show that wild-type LptE disrupts LPS-LPS interactions in vitro and that these mutations decrease the ability of LptE to disaggregate LPS. Transmission electron microscopic imaging shows that LptE can disrupt LPS aggregates even at substoichiometric concentrations. We propose a model in which LptE functions as an LPS transfer protein in the OM translocon by disaggregating LPS during transport to allow for its insertion into the OM.

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Section: Discussionmentioning

confidence: 99%

LptE binds to and alters the physical state of LPS to catalyze its assembly at the cell surface

Malojcic

Andres

Grabowicz

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…SMP-containing proteins are localized predominantly at contact sites between the ER and other organelles (18). They belong to the tubular lipid-binding protein (TULIP) superfamily comprising known lipid-binding proteins such as Takeout (19), the bactericidal/permeability-increasing protein (BPI) (20), the cholesteryl ester transfer protein (CETP) (21), and the lipopolysaccharide-binding protein (LBP) (22). The crystal structure of the SMP domain of the human extended synaptotagmin 2 protein (E-SYT2) was determined recently (23), revealing its tubular structure with a hydrophobic tunnel occupied by a phospholipid (Fig.…”

Section: Significancementioning

confidence: 99%

Conserved SMP domains of the ERMES complex bind phospholipids and mediate tether assembly

AhYoung

Jiang

Zhang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

181

207

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Membrane contact sites (MCS) between organelles are proposed as nexuses for the exchange of lipids, small molecules, and other signals crucial to cellular function and homeostasis. Various protein complexes, such as the endoplasmic reticulum-mitochondrial encounter structure (ERMES), function as dynamic molecular tethers between organelles. Here, we report the reconstitution and characterization of subcomplexes formed by the cytoplasm-exposed synaptotagmin-like mitochondrial lipid-binding protein (SMP) domains present in three of the five ERMES subunits-the soluble protein Mdm12, the endoplasmic reticulum (ER)-resident membrane protein Mmm1, and the mitochondrial membrane protein Mdm34. SMP domains are conserved lipid-binding domains found exclusively in proteins at MCS. We show that the SMP domains of Mdm12 and Mmm1 associate into a tight heterotetramer with equimolecular stoichiometry. Our 17-Å-resolution EM structure of the complex reveals an elongated crescent-shaped particle in which two Mdm12 subunits occupy symmetric but distal positions at the opposite ends of a central ER-anchored Mmm1 homodimer. Rigid body fitting of homology models of these SMP domains in the density maps reveals a distinctive extended tubular structure likely traversed by a hydrophobic tunnel. Furthermore, these two SMP domains bind phospholipids and display a strong preference for phosphatidylcholines, a class of phospholipids whose exchange between the ER and mitochondria is essential. Last, we show that the three SMP-containing ERMES subunits form a ternary complex in which Mdm12 bridges Mmm1 to Mdm34. Our findings highlight roles for SMP domains in ERMES assembly and phospholipid binding and suggest a structure-based mechanism for the facilitated transport of phospholipids between organelles.interorganelle tether | phospholipid exchange | membrane contact sites | membrane protein complex | electron microscopy

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“…In cases where Grs potentiate pathways induced by TLR ligands independent of the Gr catalytic activity (48), the focus should lie on clarifying how Grs modulate these pathways via interaction with signaling molecules. A common characteristic in LPS-enhancing proteins such as LPS-binding protein (71,72), Grs (48), the neutrophil granule protein azurocidin (73,74), high mobility group box-1 protein (75,76), protamines (77), and apolipoprotein C1 (78,79) is the presence of cationic patches of arginines and/or lysines that drive the interaction with LPS. Endocytosis may also play a role, because internalization is required for the stimulating effect of azurocidin on LPS-induced cytokine responses (80).…”

Section: Unresolved Questionsmentioning

confidence: 99%

Granzymes Regulate Proinflammatory Cytokine Responses

Wensink

Hack

Bovenschen

2015

The Journal of Immunology

120

153

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Granzymes (Grs) are serine proteases mainly produced by cytotoxic lymphocytes and are traditionally considered to cause apoptosis in tumor cells and virally infected cells. However, the cytotoxicity of several Grs is currently being debated, and additional, predominantly extracellular, functions of Grs in inflammation are emerging. Extracellular soluble Grs are elevated in the circulation of patients with autoimmune diseases and infections. Additionally, Grs are expressed by several types of immune cells other than cytotoxic lymphocytes. Recent research has revealed novel immunomodulatory functions of Grs. In this review, we provide a comprehensive overview on the role of Grs in inflammation, highlighting their role in cytokine induction and processing.

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The Crystal Structure of Lipopolysaccharide Binding Protein Reveals the Location of a Frequent Mutation that Impairs Innate Immunity

Cited by 95 publications

References 51 publications

LptE binds to and alters the physical state of LPS to catalyze its assembly at the cell surface

LptE binds to and alters the physical state of LPS to catalyze its assembly at the cell surface

Conserved SMP domains of the ERMES complex bind phospholipids and mediate tether assembly

Granzymes Regulate Proinflammatory Cytokine Responses

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