Jérôme Vicogne

Institut Pasteur de Lille, Lille, Nord-Pas-de-Calais, France

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Publications (31)129.57 Total impact

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    ABSTRACT: The development of MET receptor agonists is an important goal in regenerative medicine, but is limited by the complexity and incomplete understanding of its interaction with HGF/SF (Hepatocyte Growth Factor/Scatter Factor). NK1 is a natural occurring agonist comprising the N-terminal (N) and the first kringle (K1) domains of HGF/SF. In the presence of heparin, NK1 can self-associate into a "head to tail" dimer which is considered as the minimal structural module able to trigger MET dimerization and activation whereas isolated K1 and N domains showed a weak or a complete lack of agonistic activity respectively. Starting from these structural and biological observations, we investigated whether it was possible to recapitulate the biological properties of NK1 using a new molecular architecture of isolated N or K1 domains. Therefore, we engineered multivalent N or K1 scaffolds by combining synthetic and homogeneous site-specifically biotinylated N and K1 domains (NB and K1B) and streptavidin (S). NB alone or in complex failed to activate MET signaling and to trigger cellular phenotypes. Importantly and to the contrary of K1B alone, the semi-synthetic K1B/S complex mimicked NK1 MET agonist activity in cell scattering, morphogenesis and survival phenotypic assays. Impressively, K1B/S complex stimulated in vivo angiogenesis and, when injected in mice, protected the liver against fulminant hepatitis in a MET dependent manner whereas NK1 and HGF were substantially less potent. These data reveal that without N domain, proper multimerization of K1 domain is a promising strategy for the rational design of powerful MET agonists.
    No preview · Article · Mar 2015 · Chemical Science
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    ABSTRACT: Small ubiquitin-like modifier (SUMO) post-translational modification (PTM) of proteins has a crucial role in the regulation of important cellular processes. This protocol describes the chemical synthesis of functional SUMO-peptide conjugates. The two crucial stages of this protocol are the solid-phase synthesis of peptide segments derivatized by thioester or bis(2-sulfanylethyl)amido (SEA) latent thioester functionalities and the one-pot assembly of the SUMO-peptide conjugate by a sequential native chemical ligation (NCL)/SEA native peptide ligation reaction sequence. This protocol also enables the isolation of a SUMO SEA latent thioester, which can be attached to a target peptide or protein in a subsequent step. It is compatible with 9-fluorenylmethoxycarbonyl (Fmoc) chemistry, and it gives access to homogeneous, reversible and functional SUMO conjugates that are not easily produced using living systems. The synthesis of SUMO-peptide conjugates on a milligram scale takes 20 working days.
    No preview · Article · Feb 2015 · Nature Protocols
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    ABSTRACT: The regulation of PfPP1 phosphatase activity in Plasmodium falciparum remains to be deciphered. Data from homologous eukaryotic PP1 phosphatases suggest that several protein regulators should be involved in this essential process. One such regulator, named PfI2 based on its primary sequence homology with eukaryotic I2, was recently shown to be able to interact with PfPP1 and to inhibit its phosphatase activity, mainly through the canonical “RVxF” binding motif. The details of the structural and functional characteristics of this interaction are investigated here. Using NMR spectroscopy, a second site of interaction is suggested to reside between residues D94-T117 and contains the “FxxR/KxR/K” binding motif present in other I2 proteins. This site seems to play in concert/synergy with the “RVxF” motif to bind PP1, as only mutations in both motifs were able to abolish completely this interaction. However, regarding the structure/function relationship, the mutation of either “RVxF” or “FxxR/KxR/K” motif is more drastic, as each mutation prevents the capacity of PfI2 to trigger GVBD in micro-injected Xenopus oocytes. This indicates that the tight association of the PfI2 regulator to the PP1 phosphatase, mediated by a two-site interaction, is necessary to exert its function. Based on these results, the use of a peptide derived from the “FxxR/KxR/K” PfI2 motif was investigated for its potential effect on Plasmodium growth. This peptide, fused at its N-terminus to a penetrating sequence, was shown to accumulate specifically in infected erythrocytes and to have an anti-plasmodial effect.This article is protected by copyright. All rights reserved.Structured digital abstractPfPP1 and PfI2 bind by nuclear magnetic resonance (1, 2)PP1 physically interacts with PfPP1 by anti tag coimmunoprecipitation (View interaction)PfI2 binds to PfPP1 by enzyme linked immunosorbent assay (View interaction)PfI2 binds to PfPP1 by surface plasmon resonance (1, 2, 3, 4)
    No preview · Article · Aug 2014 · FEBS Journal
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    ABSTRACT: A bis(2-sulfanylethyl)amino PEG-based resin enabled the synthesis of large (50 Aa) SEA or thioester peptides using Fmoc-SPPS. These peptide segments permitted the first total synthesis of a 97 amino-acid long SUMO-1-SEA peptide thioester surrogate and of a functional and reversible SUMO-1 peptide conjugate.
    Preview · Article · May 2014 · Chemical Science
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    ABSTRACT: The capacity of many proteins to interact with natural or synthetic polyanions has been exploited for modulating their biological action. However, the polydispersity of these macromolecular polyanions as well as their poor specificity is a severe limitation to their use as drugs. An emerging trend in this field is the synthesis of homogeneous and well-defined polyanion-peptide conjugates which act as bivalent ligands with the peptide part bringing the selectivity of the scaffold. Alternately, this strategy can be used for improving the binding of short peptides to polyanion-binding protein targets. This work describes the design and first synthesis of homogeneous polysulfonate-peptide conjugates using thiocarbamate ligation for binding to the extracellular domain of MET tyrosine kinase receptor for hepatocyte growth factor.
    Full-text · Article · Apr 2014 · Bioconjugate Chemistry
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    ABSTRACT: Background Receptor tyrosine kinases (RTK) form a family of transmembrane proteins widely conserved in Metazoa, with key functions in cell-to-cell communication and control of multiple cellular processes. A new family of RTK named Venus Kinase Receptor (VKR) has been described in invertebrates. The VKR receptor possesses a Venus Fly Trap (VFT) extracellular module, a bilobate structure that binds small ligands to induce receptor kinase activity. VKR was shown to be highly expressed in the larval stages and gonads of several invertebrates, suggesting that it could have functions in development and/or reproduction. Results Analysis of recent genomic data has allowed us to extend the presence of VKR to five bilaterian phyla (Platyhelminthes, Arthropoda, Annelida, Mollusca, Echinodermata) as well as to the Cnidaria phylum. The presence of NveVKR in the early-branching metazoan Nematostella vectensis suggested that VKR arose before the bilaterian radiation. Phylogenetic and gene structure analyses showed that the 40 receptors identified in 36 animal species grouped monophyletically, and likely evolved from a common ancestor. Multiple alignments of tyrosine kinase (TK) and VFT domains indicated their important level of conservation in all VKRs identified up to date. We showed that VKRs had inducible activity upon binding of extracellular amino-acids and molecular modeling of the VFT domain confirmed the structure of the conserved amino-acid binding site. Conclusions This study highlights the presence of VKR in a large number of invertebrates, including primitive metazoans like cnidarians, but also its absence from nematodes and chordates. This little-known RTK family deserves to be further explored in order to determine its evolutionary origin, its possible interest for the emergence and specialization of Metazoa, and to understand its function in invertebrate development and/or reproductive biology.
    Full-text · Article · May 2013 · BMC Genomics
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    ABSTRACT: Hepatocyte growth factor/scatter factor (HGF/SF) is the high affinity ligand of MET tyrosine kinase receptor. We report here the total synthesis of a biotinylated analogue of human HGF/SF N domain. Functionally, N domain is part of the HGF/SF high affinity binding site for MET and also the main HGF/SF binding site for heparin. The 97 Aa linear chain featuring a C-terminal biotin group was assembled in high yield using an N-to-C one-pot three segments assembly strategy relying on a sequential Native Chemical Ligation (NCL)/bis(2-sulfanylethyl)amido (SEA) native peptide ligation process. The folded protein displayed the native disulfide bond pattern and showed the ability to bind heparin.
    No preview · Article · Mar 2013 · Bioorganic & medicinal chemistry
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    ABSTRACT: The GRB2-associated binder 1 (GAB1) docking/scaffold protein is a key mediator of the MET-tyrosine kinase receptor activated by hepatocyte growth factor/scatter factor (HGF/SF). Activated MET promotes recruitment and tyrosine phosphorylation of GAB1, which in turn recruits multiple proteins and mediates MET signaling leading to cell survival, motility, and morphogenesis. We previously reported that, without its ligand, MET is a functional caspase target during apoptosis, allowing the generation of a p40-MET fragment that amplifies apoptosis. In this study we established that GAB1 is also a functional caspase target by evidencing a caspase-cleaved p35-GAB1 fragment that contains the MET binding domain. GAB1 is cleaved by caspases before MET, and the resulting p35-GAB1 fragment is phosphorylated by MET upon HGF/SF binding and can interact with a subset of GAB1 partners, PI3K, and GRB2 but not with SHP2. This p35-GAB1 fragment favors cell survival by maintaining HGF/SF-induced MET activation of AKT and by hindering p40-MET pro-apoptotic function. These data demonstrate an anti-apoptotic role of caspase-cleaved GAB1 in HGF/SF-MET signaling.
    Full-text · Article · Aug 2012 · Journal of Biological Chemistry
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    ABSTRACT: The receptor tyrosine kinase Met and its ligand, the hepatocyte growth factor/scatter factor, are essential for embryonic development, whereas deregulation of Met signaling pathways is associated with tumorigenesis and metastasis. The presenilin-regulated intramembrane proteolysis (PS-RIP) is involved in ligand-independent downregulation of Met. This proteolytic process involves shedding of the Met extracellular domain followed by γ-secretase cleavage, generating labile intracellular fragments degraded by the proteasome. We demonstrate here that upon shedding both generated Met N- and C-terminal fragments are degraded directly in the lysosome, with C-terminal fragments escaping γ-secretase cleavage. PS-RIP and lysosomal degradation are complementary, because their simultaneous inhibition induces synergistic accumulation of fragments. Met N-terminal fragments associate with the high-affinity domain of HGF/SF, confirming its decoy activity which could be reduced through their routing to the lysosome at the expense of extracellular release. Finally, the DN30 monoclonal antibody inducing Met shedding promotes receptor degradation through induction of both PS-RIP and the lysosomal pathway. Thus, we demonstrate that Met shedding initiates a novel lysosomal degradation which participates to ligand-independent downregulation of the receptor.
    Full-text · Article · Jun 2012 · Traffic
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    ABSTRACT: Growing evidence indicates that the protein regulators governing protein phosphatase 1 (PP1) activity have crucial functions because their deletion drastically affects cell growth and division. PP1 has been found to be essential in Plasmodium falciparum, but little is known about its regulators. In this study, we have identified a homolog of Inhibitor-3 of PP1, named PfI3. NMR analysis shows that PfI3 belongs to the disordered protein family. High affinity interaction of PfI3 and PfPP1 is demonstrated in vitro using several methods, with an apparent dissociation constant KD of 100 nm. We further show that the conserved 41KVVRW45 motif is crucial for this interaction as the replacement of the Trp45 by an Ala45 severely decreases the binding to PfPP1. Surprisingly, PfI3 was unable to rescue a yeast strain deficient in I3 (Ypi1). This lack of functional orthology was supported as functional assays in vitro have revealed that PfI3, unlike yeast I3 and human I3, increases PfPP1 activity. Reverse genetic approaches suggest an essential role of PfI3 in the growth and/or survival of blood stage parasites because attempts to obtain knock-out parasites were unsuccessful, although the locus of PfI3 is accessible. The main localization of a GFP-tagged PfI3 in the nucleus of all blood stage parasites is compatible with a regulatory role of PfI3 on the activity of nuclear PfPP1.
    No preview · Article · Jan 2012 · Journal of Biological Chemistry
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    ABSTRACT: Three in one: Native chemical ligation (NCL) and bis(2-sulfanylethyl)amido (SEA) ligation allow the one-pot assembly of three peptide segments in the N-to-C direction. The SEA group is switched off by intramolecular disulfide bond formation during NCL. Then, a phosphine switches it on to trigger the second SEA ligation step. The K1 domain of the hepatocyte growth factor was synthesized and found to be biologically active.
    No preview · Article · Jan 2012 · Angewandte Chemie International Edition
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    ABSTRACT: The interaction of polysaccharides with proteins modulates or triggers many biological effects. In particular, heparan sulphate proteoglycans (HSPGs) have multiple regulatory interactions with growth factors, enzymes, enzyme inhibitors, and some components of the extracellular matrix. The important role played by HSPGs has motivated the synthesis and selection of HSPG mimetics for modulating the biological activity of HS-binding proteins. We present hereinafter an efficient polysaccharide microarray method that allows the screening of HS-mimetic libraries towards HS-binding growth factors, a major class of polypeptides whose inhibition or potentiation is of high medical interest.
    Full-text · Article · Jan 2012 · Methods in molecular biology (Clifton, N.J.)
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    ABSTRACT: Growing evidence indicates that the protein regulators governing protein phosphatase 1 (PP1) activity have crucial functions because their deletion drastically affects cell growth and division. PP1 has been found to be essential in Plasmodium falciparum, but little is known about its regulators. In this study, we have identified a homolog of Inhibitor-3 of PP1, named PfI3. NMR analysis shows that PfI3 belongs to the disordered protein family. High affinity interaction of PfI3 and PfPP1 is demonstrated in vitro using several methods, with an apparent dissociation constant KD of 100 nm. We further show that the conserved 41KVVRW45 motif is crucial for this interaction as the replacement of the Trp45 by an Ala45 severely decreases the binding to PfPP1. Surprisingly, PfI3 was unable to rescue a yeast strain deficient in I3 (Ypi1). This lack of functional orthology was supported as functional assays in vitro have revealed that PfI3, unlike yeast I3 and human I3, increases PfPP1 activity. Reverse genetic approaches suggest an essential role of PfI3 in the growth and/or survival of blood stage parasites because attempts to obtain knock-out parasites were unsuccessful, although the locus of PfI3 is accessible. The main localization of a GFP-tagged PfI3 in the nucleus of all blood stage parasites is compatible with a regulatory role of PfI3 on the activity of nuclear PfPP1.
    Full-text · Article · Nov 2011 · Journal of Biological Chemistry
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    ABSTRACT: The juxtamembrane domain of vesicle-associated membrane protein (VAMP) 2 (also known as synaptobrevin2) contains a conserved cluster of basic/hydrophobic residues that may play an important role in membrane fusion. Our measurements on peptides corresponding to this domain determine the electrostatic and hydrophobic energies by which this domain of VAMP2 could bind to the adjacent lipid bilayer in an insulin granule or other transport vesicle. Mutation of residues within the juxtamembrane domain that reduce the VAMP2 net positive charge, and thus its interaction with membranes, inhibits secretion of insulin granules in beta cells. Increasing salt concentration in permeabilized cells, which reduces electrostatic interactions, also results in an inhibition of insulin secretion. Similarly, amphipathic weak bases (e.g., sphingosine) that reverse the negative electrostatic surface potential of a bilayer reverse membrane binding of the positively charged juxtamembrane domain of a reconstituted VAMP2 protein and inhibit membrane fusion. We propose a model in which the positively charged VAMP and syntaxin juxtamembrane regions facilitate fusion by bridging the negatively charged vesicle and plasma membrane leaflets.
    Preview · Article · Oct 2009 · Molecular biology of the cell
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    ABSTRACT: Schistosomiasis (bilharzia) is a parasitic disease of worldwide significance affecting human and animals. As schistosome eggs are responsible for pathogenesis, the understanding of processes controlling gonad development might open new perspectives for intervention. The Src-like tyrosine-kinase SmTK3 of Schistosoma mansoni is expressed in the gonads, and its pharmacological inhibition reduces mitogenic activity and egg production in paired females in vitro. Since Src kinases are important signal transduction proteins it is of interest to unravel the signaling cascades SmTK3 is involved in to understand its cellular role in the gonads.
    Full-text · Article · Sep 2009 · PLoS ONE
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    ABSTRACT: In beta-cells of the pancreas, the glucose transporter (GLUT)-2 facilitative glucose transporter protein is localized to the plasma membrane and functions as part of the glucose sensing mechanism for the stimulation of insulin secretion. We observed that expressed GLUT2 protein in the cultured Min6B1 cell line undergoes enhanced endocytosis at high extracellular glucose concentrations that stimulate insulin secretion. Moreover, the internalized GLUT2 protein undergoes rapid degradation induced by chronic high-glucose or arginine stimulation but does not undergo plasma membrane recycling or accumulation in any microscopically apparent intracellular membrane compartment. The rapid degradation of GLUT2 was prevented by lysosomal inhibition (chloroquine) concomitant with the accumulation of GLUT2 in endomembrane structures. In contrast, neither endocytosis nor the lack of internal membrane localized GLUT2 remained completely unaffected by proteosomal inhibition (lactacystin) or an heat shock protein-90 inhibitor (geldanamycin). Moreover, the endocytosis and degradation of GLUT2 was specific for beta-cells because expression of GLUT2 in 3T3L1 adipocytes remained cell surface localized and did not display a rapid rate of degradation. Together, these data demonstrate that hyperglycemia directly affects beta-cell function and activates a trafficking pathway that results in the rapid endocytosis and degradation of the cell surface GLUT2 glucose transporter.
    No preview · Article · Jun 2009 · Endocrinology
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    A Ahier · N Khayath · J Vicogne · C Dissous
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    ABSTRACT: Very little is known about insulin signalling in schistosomes despite its potential importance in host-parasite molecular dialogue and parasite growth and development. The recent characterization of two insulin receptors (SmIR-1 and SmIR-2) in Schistosoma mansoni has led us to reconsider the question of the potential importance of insulin in host-schistosome interactions. In this work, we demonstrated that insulin could regulate glucose uptake in schistosomes and we investigated the implication of SmIR-1 and SmIR-2 in this process. The possibility that specific inhibitors of SmIR-1 and SmIR-2 tyrosine kinase activities could be developed to target schistosomes is discussed.
    Preview · Article · Jan 2009 · Parasite
  • Jérôme Vicogne · Jeffrey E Pessin
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    ABSTRACT: Lipid-mixing assay is now commonly used to study protein, temperature and ion-dependent membrane fusion events. This assay has been crucial to demonstrate the ability of neuronal and non-neuronal soluble NSF attachment receptor (SNARE) to promote spontaneous fusion of liposomes. This lipid-mixing assay is based on the fluorescence resonance energy transfer (FRET) capability between a donor fluorescent lipid and a quenching lipid. When fusion between donor fluorescent liposomes and nonfluorescent acceptor liposome occurred, FRET decreases. This assay allows a real-time reading of SNARE-mediated liposome fusion.
    No preview · Article · Feb 2008 · Methods in Molecular Biology
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    ABSTRACT: Insulin signalling is a very ancient and well conserved pathway in metazoan cells, dependent on insulin receptors (IR) which are transmembrane proteins with tyrosine kinase activity. A unique IR is usually present in invertebrates whereas two IR members are found with different functions in vertebrates. This work demonstrates the existence of two distinct IR homologs (SmIR-1 and SmIR-2) in the parasite trematode Schistosoma mansoni. These two receptors display differences in several structural motifs essential for signalling and are differentially expressed in parasite tissues, suggesting that they could have distinct functions. The gene organization of SmIR-1 and SmIR-2 is similar to that of the human IR and to that of the IR homolog from Echinococcus multilocularis (EmIR), another parasitic platyhelminth. SmIR-1 and SmIR-2 were shown to interact with human pro-insulin but not with pro-insulin-like growth factor-1 in two-hybrid assays. Phylogenetic results indicated that SmIR-2 and EmIR might be functional orthologs whereas SmIR-1 would have emerged to fulfil specific functions in schistosomes.
    Full-text · Article · Mar 2007 · FEBS Journal
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    ABSTRACT: Insulin-stimulated glucose uptake requires the fusion of GLUT4 transporter-containing vesicles with the plasma membrane, a process that depends on the SNARE (soluble N-ethylmaleimide-sensitive fusion factor attachment receptor) proteins VAMP2 (vesicle-associated membrane protein 2) and syntaxin 4 (Stx4)/SNAP23 (soluble N-ethylmaleimide-sensitive fusion factor attachment protein 23). Efficient SNARE-dependent fusion has been shown in many settings in vivo to require the generation of both phosphatidylinositol-4,5-bisphosphate (PIP2) and phosphatidic acid (PA). Addition of PA to Stx4/SNAP23 vesicles markedly enhanced the fusion rate, whereas its addition to VAMP2 vesicles was inhibitory. In contrast, addition of PIP2 to Stx4/SNAP23 vesicles inhibited the fusion reaction, and its addition to VAMP2 vesicles was stimulatory. The optimal distribution of phospholipids was found to trigger the progression from the hemifused state to full fusion. These findings reveal an unanticipated dependence of SNARE complex-mediated fusion on asymmetrically distributed acidic phospholipids and provide mechanistic insights into the roles of phospholipase D and PIP kinases in the late stages of regulated exocytosis.
    Preview · Article · Nov 2006 · Proceedings of the National Academy of Sciences

Publication Stats

649 Citations
129.57 Total Impact Points

Institutions

  • 2001-2015
    • Institut Pasteur de Lille
      Lille, Nord-Pas-de-Calais, France
  • 2012-2014
    • University of Lille Nord de France
      Lille, Nord-Pas-de-Calais, France
  • 2005-2014
    • Institut de Biologie de Lille
      Lille, Nord-Pas-de-Calais, France
  • 2009
    • Albert Einstein College of Medicine
      • Department of Physiology & Biophysics
      New York City, New York, United States
  • 2008
    • Stony Brook University
      • Department of Pharmacological Sciences
      스토니브룩, New York, United States