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Institut de Biologie StructuraleGrenoble / France

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Presentation of the Structure and Activity of Glycosaminoglycans Group

Group leader : Hugues Lortat-Jacob

The SAGAG group is composed of 2 teams :

Members

Permanent members :

  • Hugues Lortat-Jacob (DRCE2 CNRS)
  • Rabia Sadir (Engineer CEA)
  • Romain Vivès (DR2 CNRS)
  • Rebekka Wild (CRCN CNRS)
  • Evelyne Gout (IE CNRS)

Contractual members :

  • Thibault Annaval (Post-doc ; Septembre 2019 - March 2022)
  • Rana El Masri (PhD student ; February 2016- January 2020)
  • Yoann Crétinon (PhD student ; October 2019- September 2022

Le SAGAG

Research topics

Our researches focus on a group of polysaccharides collectively known as glycosaminoglycans (GAGs) which comprise heparin, heparan sulphate, chondroitin and dermatan sulphate, keratan sulphate and hyaluronic acid.

GAGs are widely distributed in vivo. They are present in large amounts in every tissue both at the cell surface, where they importantly contribute to the glycocalix, and within the extracellular matrix. They exert their biological functions by interacting with a large array of proteins (cytokines, growth factors …) thereby modifying their structure and reactivity. Present at the cell - extracellular milieu interface, GAGs are strategically located to regulate most of the processes that occur at the cell membrane level (cell-cell communication, signalling, cell-matrix interactions, interactions with pathogens …).

In that context, our work aims in particular at :

  • Identifying the structural determinants involved in GAG-protein binding reactions.
  • Understanding the cellular mechanisms regulating the saccharide structure of GAGs.
  • Describing the mechanisms by which GAGs control protein activities.

The experimental models used are (1) pathogen attachment and entry into host cells and (2) the immune system. The characterisation of complexes between viral/bacterial proteins or cytokines and GAGs leads to the engineering of anti-infectious or anti-inflammatory oligosaccharides.
In addition, a number of methodological approaches (including GAG-on-chip ; sequencing ; NMR) are developed for the analysis of GAG/protein interactions.

Key word : Glycosaminoglycan - heparan sulfate - Glycobiology - Receptor - Interaction - Cytokines - Immunity - Host-Pathogen interactions – Virology - Infectious diseases - Chemo-enzymatic approaches - Methods developments

Specific techniques

  • Production, purification, biochemical and structural characterisation of glycosaminoglycans
  • Production, purification and characterisation of recombinant proteins
  • Cellular biology
  • Kinetic analysis of interactions (BIAcore technology)
  • Peptide sequencing at the protein-glycosaminoglycan interface
  • NMR based structural approaches.

Available services

Disaccharide analysis of glycosaminoglycans

Major publications

  • Debarnot C., Monneau Y.R., Roig-Zamboni V., Delauzun V., Le Narvor C., Richard E., Hénault J., Goulet A., Fadel F., Vivès R.R., Priem B., Bonnaffé D., Lortat-Jacob H., Bourne Y. Structural insights into substrate binding and catalytic mechanism of human heparan sulfate D-glucuronyl C5 epimerase.
    Proc. Natl. Acad. Sci. USA 116, 6760-6765 (2019)
  • Seffouh A., El Masri R., Makshakova O., Gout E., El Oula Hassoun Z., Andrieu J.P., Lortat-Jacob H. and Vivès R.R. Expression and purification of recombinant extracellular sulfatase Hsulf-2 allows deciphering of enzyme sub-domains coordinated role for the binding and 6-O-desulfation of heparan sulfate.
    Cell. Mol. Life Sci. 76, 1807-1819 (2019)
  • Przybylski C, Bonnet V, Vivès RR. A microscale double labelling of GAG oligosaccharides compatible with enzymatic treatment and mass spectrometry. Chem Commun (Camb). 55, 4182-4185 (2019)
  • Monneau Y.R., Luo L., Sankaranarayanan N.V., Nagarajan B., Vivès R.R., Baleux F., Desai U.R., Arenzana-Seidedos F. and Lortat-Jacob H. Solution structure of CXCL13 and heparan sulphate binding show that GAG binding site and biological activity rely on distinct domains.
    Open Biology 7, 170133 (2017)
  • Arien K.K., Baleux F., Desjardins D., Porrot F., Coic Y.-M., Michiels J., Bouchemal K., Bonnaffé D., Bruel T., Schwartz O., Le Grand R., Vanham G., Dereuddre-Bosquet N. and Lortat-Jacob H. CD4-mimetic sulfopeptide conjugates display sub-nanomolar anti-HIV-1 activity and protect macaques against a SHIV162P3 vaginal challenge. Scientific Reports 6, 34829 (2016)
  • Connell B.J., Sadir R., Baleux F., Laguri C., Kleman J-P., Luo L., Arenzana-Seisdedos F. and Lortat-Jacob H. Heparan Sulfate differently regulates CXCL12α and CXCL12γ mediated chemotaxis through differential presentation to CXCR4. Science Signaling 9, ra107 (2016)
  • Préchoux A., Halimi C., Simorre J.P., Lortat-Jacob H. and Laguri C. C5-epimerase and 2-O-sulfotransferase associate in vitro to generate contiguous epimerized and 2-O-sulfated heparan sulfate domains. ACS ChemBiol 10, 1064-1071 (2015)
  • Vivès R.R., Seffouh A. and Lortat-Jacob H. Post-synthetic regulation of Heparan Sulfate structure : the yin and yang of the Sulfs in Cancer. Front. Oncol. 3:331. doi : 10.3389/fonc.2013.00331 (2014)
  • Saesen E, Sarrazin S, Laguri C, Sadir R, Maurin D, Thomas A, Imberty A and Lortat-Jacob H. Insights into the mechanism by which Interferon-gamma basic amino acid clusters mediate protein binding to heparan sulfate. J. Am. Chem. Soc. 135, 9384−9390 (2013)
  • Seffouh A, Milz F, Przybylski C, Laguri C, Oosterhof A, Bourcier S, Sadir R, Dutkowski E, Daniel R, van Kuppevelt TH, Dierks T, Lortat-Jacob H, and Vivès RR. HSulf sulfatases catalyse processive and orientated 6-O-desulfation of heparan sulfate that differentially regulate fibroblast growth factor activity FASEB J. 27, 2431-2439
    (2013)
  • Connell BJ, Baleux F, Coic YM, Clayette P, Bonnaffé D and Lortat-Jacob H. A synthetic heparan sulfate-mimetic peptide conjugated to a mini CD4 displays very high anti-HIV-1 activity independently of coreceptor usage. Chemistry & Biology 19, 131-139 (2012)
  • Laguri C, Sapay N, Simorre J-P, Brutscher B, Imberty A, Gans P and and Lortat-Jacob H. 13C-labeled heparan sulfate analogue as a tool to study protein/heparan sulfate interaction by NMR spectroscopy. Application to the CXCL12α chemokine. J. Am. Chem. Soc. 133, 9642-9645 (2011)
  • Baleux F, Loureiro-Morais L, Hersant Y, Clayette P, Arenzana-Seisdedos F, Bonnaffé B and Lortat-Jacob H. A synthetic CD4-HS glycoconjugate inhibits both CCR5 and CXCR4 HIV-1 attachment and entry. Nat. Chem. Biol. 5, 743-748 (2009)
  • Lortat-Jacob H. The molecular basis and functional implications of chemokine interactions with heparan sulphate. Curr. Opin. Struct. Biol. 19, 543-548 (2009)
  • Sarrazin S, Bonnaffé D, Lubineau A, and Lortat-Jacob H. Heparan sulfate mimicry : A synthetic glycoconjugate that recognizes the heparin-binding domain of IFNγ inhibits the cytokine activity. J. Biol. Chem. 280, 37558-37564 (2005)
  • Lortat-Jacob H, Grosdidier A, and Imberty A. Structural diversity of heparan sulphate binding domains in chemokines. Proc. Natl. Acad. Sci. USA 99, 1229-1234 (2002)
  • Reeves EP, Lu H, Lortat-Jacob H, Messina CGM, Bolsover S, Gabella G, Potma EO, Warley A, Roes J, and Segal AW. Killing activity of neutrophils is mediated through activation of proteases by K+ flux. Nature 416, 291 - 297 (2002)

A list of all publications since 2000 can be found here.

Thesis

A list of Ph.Ds. can be found here.