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E Y Jones - One of the best experts on this subject based on the ideXlab platform.
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neuropilins lock secreted semaphorins onto plexins in a ternary signaling complex
Nature Structural & Molecular Biology, 2012Co-Authors: Janssen Bjc, T Malinauskas, Greg A Weir, M Z Cader, Christian Siebold, E Y JonesAbstract:Co-Receptors add complexity to cell-cell signaling systems. The secreted semaphorin 3s (Sema3s) require a Co-Receptor, neuropilin (Nrp), to signal through plexin As (PlxnAs) in functions ranging from axon guidance to bone homeostasis, but the Co-Receptor’s role is obscure. Here we present the low resolution crystal structure of a mouse semaphorin-plexin-Nrp complex alongside unliganded component structures. Dimeric semaphorin, two copies of plexin and two copies of Nrp are arranged as a dimer of heterotrimers. In each heterotrimer sub-complex semaphorin contacts plexin as in Co-Receptor independent signaling complexes. The Nrp1s cross-brace the assembly, bridging between sema domains of the Sema3A and PlxnA2 subunits from the two heterotrimers. Biophysical and cellular analyses confirm that this Nrp binding mode stabilizes a canonical, but weakened Sema3-PlxnA interaction, adding Co-Receptor control over the mechanism by which receptor dimerization and/or oligomerization triggers signaling.
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Neuropilins lock secreted semaphorins onto plexins in a ternary signaling complex
Nature Structural & Molecular Biology, 2012Co-Authors: Bert J C Janssen, T Malinauskas, Greg A Weir, M Z Cader, Christian Siebold, E Y JonesAbstract:Semaphorin-plexin cell-cell signaling is important in tissue development, with roles in axon guidance, immunity and cancer. The structure of the complex formed between semaphorin-3, plexin-A and their Co-Receptor neuropilin, combined with mutagenesis, reveals how neuropilin contributes to stabilizing the signaling complex. Co-Receptors add complexity to cell-cell signaling systems. The secreted semaphorin 3s (Sema3s) require a Co-Receptor, neuropilin (Nrp), to signal through plexin As (PlxnAs) in functions ranging from axon guidance to bone homeostasis, but the role of the Co-Receptor is obscure. Here we present the low-resolution crystal structure of a mouse semaphorin–plexin–Nrp complex alongside unliganded component structures. Dimeric semaphorin, two copies of plexin and two copies of Nrp are arranged as a dimer of heterotrimers. In each heterotrimer subcomplex, semaphorin contacts plexin, similar to in Co-Receptor–independent signaling complexes. The Nrp1s cross brace the assembly, bridging between sema domains of the Sema3A and PlxnA2 subunits from the two heterotrimers. Biophysical and cellular analyses confirm that this Nrp binding mode stabilizes a canonical, but weakened, Sema3–PlxnA interaction, adding Co-Receptor control over the mechanism by which receptor dimerization and/or oligomerization triggers signaling.
Peter Laudrup - One of the best experts on this subject based on the ideXlab platform.
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Metabotropic excitatory amino acid receptor agonists selectively potentiate behavioral effects induced by ionotropic excitatory amino acid receptor agonists in mice.
European Journal of Pharmacology, 1993Co-Authors: Henrik Klitgaard, Peter LaudrupAbstract:Abstract The behavioral consequences of co-activation of metabotropic and ionotropic excitatory amino acid receptors were studied in mice using intracerebroventricular (i.c.v.) co-infusion of the metabotropic receptor agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylate (1S,3R-ACPD) with the subtype-specific ionotropic receptor agonists N- methyl - d - aspartate (NMDA), kainate and α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA). I.c.v. co-infusion of ionotropic receptor agonists (0.3–3 nmol/min) with a fixed dose of 1S,3R-ACPD (144 nmol/min) decreased time to onset of clonic convulsions (P
Carmen Ortiz Mellet - One of the best experts on this subject based on the ideXlab platform.
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sp2-Iminosugar glycolipids as inhibitors of lipopolysaccharide-mediated human dendritic cell activation in vitro and of acute inflammation in mice in vivo
European Journal of Medicinal Chemistry, 2019Co-Authors: Evelyne Schaeffer, Elena Sánchez-fernández, Rita Gonçalves-pereira, Vincent Flacher, Delphine Lamon, Monique Duval, Jean-daniel Fauny, José Garcia Fernandez, Christopher Mueller, Carmen Ortiz MelletAbstract:Glycolipid mimetics consisting of a bicyclic polyhydroxypiperidine-cyclic carbamate core and a pseu-doanomeric hydrophobic tail, termed sp 2-iminosugar glycolipids (sp 2-IGLs), target microglia during neuroinflammatory processes. Here we have synthesized and investigated new variants of sp 2-IGLs for their ability to suppress the activation of human monocyte-derived dendritic cells (DCs) by lipopoly-saccharide (LPS) signaling through Toll-like receptor 4. We report that the best lead was (1R)-1-dodecylsulfonyl-5N,6O-oxomethylidenenojirimycin (DSO 2-ONJ), able to inhibit LPS-induced TNFa production and maturation of DCs. Immunovisualization experiments, using a mannoside glycolipid conjugate (MGC) that also suppress LPS-mediated DC activation as control, evidenced a distinct mode of action for the sp 2-IGLs: unlike MGCs, DSO 2-ONJ did not elicit internalization of the LPS Co-Receptor CD14 or induce its co-localization with the Toll-like receptor 4. In a mouse model of LPS-induced acute inflammation, DSO 2-ONJ demonstrated anti-inflammatory activity by inhibiting the production of the pro-inflammatory interleukin-6. The ensemble of the data highlights sp 2-IGLs as a promising new class of molecules against inflammation by interfering in Toll-like receptor intracellular signaling.
Christof Niehrs - One of the best experts on this subject based on the ideXlab platform.
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The complex world of WNT receptor signalling
Nature Reviews Molecular Cell Biology, 2012Co-Authors: Christof NiehrsAbstract:30 years after the identification of WNTs, their signal transduction has become increasingly complex, with the discovery of more than 15 receptors and Co-Receptors in seven protein families. The recent discovery of three receptor classes for the R-spondin family of WNT agonists further adds to this complexity. What emerges is an intricate network of receptors that form higher-order ligand–receptor complexes routing downstream signalling. These are regulated both extracellularly by agonists such as R-spondin and intracellularly by post-translational modifications such as phosphorylation, proteolytic processing and endocytosis. There is bewildering complexity in WNT signal transduction at the cell surface. 19 WNT proteins couple to more than 15 receptors and Co-Receptors in seven protein families: Frizzled, low-density lipoprotein receptor-related protein 5 (LRP5) and LRP6, receptor Tyr kinase-like orphan receptor 1 (ROR1) and ROR2, protein Tyr kinase 7 (PTK7), receptor Tyr kinase (RYK), muscle skeletal receptor Tyr kinase (MUSK) and the heparan sulphate proteoglycans syndecan and glypican. Frizzled proteins act as principal WNT receptors and recruit different Co-Receptors to engage specific subpathways. WNT receptors and Co-Receptors are regulated intracellularly by phosphorylation, proteolytic processing and endocytosis. Endocytosis is a key mechanism, and WNT signalling requires endocytosis, endosomal signalosomes and multivesicular bodies. Agonists (R-spondins) and antagonists (Dickkopf-related protein 1 (DKK1) and Kremen) regulate receptor and Co-Receptor internalization to modulate WNT signalling. The R-spondin family of WNT agonists acts via downstream transmembrane proteins, inlcuding syndecans, Leu-rich repeat-containing G-protein coupled receptor 4 (LGR4) and LGR6 and transmembrane E3 ubiquitin ligases RNF43 and ZNRF3. Since the discovery of WNTs 30 years ago, it has become clear that this signalling pathway is incredibly complex, using more than 15 receptors and Co-Receptors. What has emerged is that these proteins form higher-order ligand–receptor complexes that transduce downstream signalling and influence numerous cellular processes.
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The complex world of WNT receptor signalling
Nature Reviews Molecular Cell Biology, 2012Co-Authors: Christof NiehrsAbstract:30 years after the identification of WNTs, their signal transduction has become increasingly complex, with the discovery of more than 15 receptors and Co-Receptors in seven protein families. The recent discovery of three receptor classes for the R-spondin family of WNT agonists further adds to this complexity. What emerges is an intricate network of receptors that form higher-order ligand–receptor complexes routing downstream signalling. These are regulated both extracellularly by agonists such as R-spondin and intracellularly by post-translational modifications such as phosphorylation, proteolytic processing and endocytosis. Since the discovery of WNTs 30 years ago, it has become clear that this signalling pathway is incredibly complex, using more than 15 receptors and Co-Receptors. What has emerged is that these proteins form higher-order ligand–receptor complexes that transduce downstream signalling and influence numerous cellular processes. There is bewildering complexity in WNT signal transduction at the cell surface. 19 WNT proteins couple to more than 15 receptors and Co-Receptors in seven protein families: Frizzled, low-density lipoprotein receptor-related protein 5 (LRP5) and LRP6, receptor Tyr kinase-like orphan receptor 1 (ROR1) and ROR2, protein Tyr kinase 7 (PTK7), receptor Tyr kinase (RYK), muscle skeletal receptor Tyr kinase (MUSK) and the heparan sulphate proteoglycans syndecan and glypican. Frizzled proteins act as principal WNT receptors and recruit different Co-Receptors to engage specific subpathways. WNT receptors and Co-Receptors are regulated intracellularly by phosphorylation, proteolytic processing and endocytosis. Endocytosis is a key mechanism, and WNT signalling requires endocytosis, endosomal signalosomes and multivesicular bodies. Agonists (R-spondins) and antagonists (Dickkopf-related protein 1 (DKK1) and Kremen) regulate receptor and Co-Receptor internalization to modulate WNT signalling. The R-spondin family of WNT agonists acts via downstream transmembrane proteins, inlcuding syndecans, Leu-rich repeat-containing G-protein coupled receptor 4 (LGR4) and LGR6 and transmembrane E3 ubiquitin ligases RNF43 and ZNRF3.
David R Poyner - One of the best experts on this subject based on the ideXlab platform.
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novel peptide antagonists of adrenomedullin and calcitonin gene related peptide receptors identification pharmacological characterization and interactions with position 74 in receptor activity modifying protein 1 3
Journal of Pharmacology and Experimental Therapeutics, 2009Co-Authors: Samuel D Robinson, Richard J. Bailey, Jacqueline F Aitken, David R PoynerAbstract:Human adrenomedullin (AM) is a 52-amino acid peptide belonging to the calcitonin peptide family, which also includes calcitonin gene-related peptide (CGRP) and AM2. The two AM receptors, AM(1) and AM(2), are calcitonin receptor-like receptor (CL)/receptor activity-modifying protein (RAMP) (RAMP2 and RAMP3, respectively) heterodimers. CGRP receptors comprise CL/RAMP1. The only human AM receptor antagonist (AM(22-52)) is a truncated form of AM; it has low affinity and is only weakly selective for AM(1) over AM(2) receptors. To develop novel AM receptor antagonists, we explored the importance of different regions of AM in interactions with AM(1), AM(2), and CGRP receptors. AM(22-52) was the framework for generating further AM fragments (AM(26-52) and AM(30-52)), novel AM/alphaCGRP chimeras (C1-C5 and C9), and AM/AM(2) chimeras (C6-C8). cAMP assays were used to screen the antagonists at all receptors to determine their affinity and selectivity. Circular dichroism spectroscopy was used to investigate the secondary structures of AM and its related peptides. The data indicate that the structures of AM, AM2, and alphaCGRP differ from one another. Our chimeric approach enabled the identification of two nonselective high-affinity antagonists of AM(1), AM(2), and CGRP receptors (C2 and C6), one high-affinity antagonist of AM(2) receptors (C7), and a weak antagonist selective for the CGRP receptor (C5). By use of receptor mutagenesis, we also determined that the C-terminal nine amino acids of AM seem to be responsible for its interaction with Glu74 of RAMP3. We provide new information on the structure-activity relationship of AM, alphaCGRP, and AM2 and how AM interacts with CGRP and AM(2) receptors.