High affinity sugar ligands of C-type lectin receptor langerin

Fumi Ota, Tetsuya Hirayama, Yasuhiko Kizuka, Yoshiki Yamaguchi, Reiko Fujinawa, Masahiro Nagata, Hendra S. Ismanto, Bernd Lepenies, Jonas Aretz, Christoph Rademacher, Peter H. Seeberger, Takashi Angata, Shinobu Kitazume, Keiichi Yoshida, Tomoko Betsuyaku, Kozui Kida, Shou Yamasaki, Naoyuki Taniguchi

    Research output: Contribution to journalArticle

    3 Citations (Scopus)

    Abstract

    Background: Langerin, a C-type lectin receptor (CLR) expressed in a subset of dendritic cells (DCs), binds to glycan ligands for pathogen capture and clearance. Previous studies revealed that langerin has an unusual binding affinity toward 6-sulfated galactose (Gal), a structure primarily found in keratan sulfate (KS). However, details and biological outcomes of this interaction have not been characterized. Based on a recent discovery that the disaccharide L4, a KS component that contains 6-sulfo-Gal, exhibits anti-inflammatory activity in mouse lung, we hypothesized that L4-related compounds are useful tools for characterizing the langerin-ligand interactions and their therapeutic application. Methods: We performed binding analysis between purified long and short forms of langerin and a series of KS disaccharide components. We also chemically synthesized oligomeric derivatives of L4 to develop a new high-affinity ligand of langerin. Results: We show that the binding critically requires the 6-sulfation of Gal and that the long form of langerin displays higher affinity than the short form. The synthesized trimeric (also designated as triangle or Tri) and polymeric (pendant) L4 derivatives displayed over 1000-fold higher affinity toward langerin than monomeric L4. The pendant L4, but not the L4 monomer, was found to effectively transduce langerin signaling in a model cell system. Conclusions: L4 is a specific ligand for langerin. Oligomerization of L4 unit increased the affinity toward langerin. General significance: These results suggest that oligomeric L4 derivatives will be useful for clarifying the langerin functions and for the development of new glycan-based anti-inflammatory drugs.

    Original languageEnglish
    Pages (from-to)1592-1601
    Number of pages10
    JournalBiochimica et Biophysica Acta - General Subjects
    Volume1862
    Issue number7
    DOIs
    Publication statusPublished - Jul 1 2018

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    C-Type Lectins
    Keratan Sulfate
    Sugars
    Galactose
    Ligands
    Disaccharides
    Derivatives
    Polysaccharides
    Anti-Inflammatory Agents
    Oligomerization
    Pathogens
    Dendritic Cells
    Monomers
    Lung
    Pharmaceutical Preparations

    All Science Journal Classification (ASJC) codes

    • Biophysics
    • Biochemistry
    • Molecular Biology

    Cite this

    Ota, F., Hirayama, T., Kizuka, Y., Yamaguchi, Y., Fujinawa, R., Nagata, M., ... Taniguchi, N. (2018). High affinity sugar ligands of C-type lectin receptor langerin. Biochimica et Biophysica Acta - General Subjects, 1862(7), 1592-1601. https://doi.org/10.1016/j.bbagen.2018.04.004

    High affinity sugar ligands of C-type lectin receptor langerin. / Ota, Fumi; Hirayama, Tetsuya; Kizuka, Yasuhiko; Yamaguchi, Yoshiki; Fujinawa, Reiko; Nagata, Masahiro; Ismanto, Hendra S.; Lepenies, Bernd; Aretz, Jonas; Rademacher, Christoph; Seeberger, Peter H.; Angata, Takashi; Kitazume, Shinobu; Yoshida, Keiichi; Betsuyaku, Tomoko; Kida, Kozui; Yamasaki, Shou; Taniguchi, Naoyuki.

    In: Biochimica et Biophysica Acta - General Subjects, Vol. 1862, No. 7, 01.07.2018, p. 1592-1601.

    Research output: Contribution to journalArticle

    Ota, F, Hirayama, T, Kizuka, Y, Yamaguchi, Y, Fujinawa, R, Nagata, M, Ismanto, HS, Lepenies, B, Aretz, J, Rademacher, C, Seeberger, PH, Angata, T, Kitazume, S, Yoshida, K, Betsuyaku, T, Kida, K, Yamasaki, S & Taniguchi, N 2018, 'High affinity sugar ligands of C-type lectin receptor langerin', Biochimica et Biophysica Acta - General Subjects, vol. 1862, no. 7, pp. 1592-1601. https://doi.org/10.1016/j.bbagen.2018.04.004
    Ota F, Hirayama T, Kizuka Y, Yamaguchi Y, Fujinawa R, Nagata M et al. High affinity sugar ligands of C-type lectin receptor langerin. Biochimica et Biophysica Acta - General Subjects. 2018 Jul 1;1862(7):1592-1601. https://doi.org/10.1016/j.bbagen.2018.04.004
    Ota, Fumi ; Hirayama, Tetsuya ; Kizuka, Yasuhiko ; Yamaguchi, Yoshiki ; Fujinawa, Reiko ; Nagata, Masahiro ; Ismanto, Hendra S. ; Lepenies, Bernd ; Aretz, Jonas ; Rademacher, Christoph ; Seeberger, Peter H. ; Angata, Takashi ; Kitazume, Shinobu ; Yoshida, Keiichi ; Betsuyaku, Tomoko ; Kida, Kozui ; Yamasaki, Shou ; Taniguchi, Naoyuki. / High affinity sugar ligands of C-type lectin receptor langerin. In: Biochimica et Biophysica Acta - General Subjects. 2018 ; Vol. 1862, No. 7. pp. 1592-1601.
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    abstract = "Background: Langerin, a C-type lectin receptor (CLR) expressed in a subset of dendritic cells (DCs), binds to glycan ligands for pathogen capture and clearance. Previous studies revealed that langerin has an unusual binding affinity toward 6-sulfated galactose (Gal), a structure primarily found in keratan sulfate (KS). However, details and biological outcomes of this interaction have not been characterized. Based on a recent discovery that the disaccharide L4, a KS component that contains 6-sulfo-Gal, exhibits anti-inflammatory activity in mouse lung, we hypothesized that L4-related compounds are useful tools for characterizing the langerin-ligand interactions and their therapeutic application. Methods: We performed binding analysis between purified long and short forms of langerin and a series of KS disaccharide components. We also chemically synthesized oligomeric derivatives of L4 to develop a new high-affinity ligand of langerin. Results: We show that the binding critically requires the 6-sulfation of Gal and that the long form of langerin displays higher affinity than the short form. The synthesized trimeric (also designated as triangle or Tri) and polymeric (pendant) L4 derivatives displayed over 1000-fold higher affinity toward langerin than monomeric L4. The pendant L4, but not the L4 monomer, was found to effectively transduce langerin signaling in a model cell system. Conclusions: L4 is a specific ligand for langerin. Oligomerization of L4 unit increased the affinity toward langerin. General significance: These results suggest that oligomeric L4 derivatives will be useful for clarifying the langerin functions and for the development of new glycan-based anti-inflammatory drugs.",
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    AU - Ota, Fumi

    AU - Hirayama, Tetsuya

    AU - Kizuka, Yasuhiko

    AU - Yamaguchi, Yoshiki

    AU - Fujinawa, Reiko

    AU - Nagata, Masahiro

    AU - Ismanto, Hendra S.

    AU - Lepenies, Bernd

    AU - Aretz, Jonas

    AU - Rademacher, Christoph

    AU - Seeberger, Peter H.

    AU - Angata, Takashi

    AU - Kitazume, Shinobu

    AU - Yoshida, Keiichi

    AU - Betsuyaku, Tomoko

    AU - Kida, Kozui

    AU - Yamasaki, Shou

    AU - Taniguchi, Naoyuki

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    N2 - Background: Langerin, a C-type lectin receptor (CLR) expressed in a subset of dendritic cells (DCs), binds to glycan ligands for pathogen capture and clearance. Previous studies revealed that langerin has an unusual binding affinity toward 6-sulfated galactose (Gal), a structure primarily found in keratan sulfate (KS). However, details and biological outcomes of this interaction have not been characterized. Based on a recent discovery that the disaccharide L4, a KS component that contains 6-sulfo-Gal, exhibits anti-inflammatory activity in mouse lung, we hypothesized that L4-related compounds are useful tools for characterizing the langerin-ligand interactions and their therapeutic application. Methods: We performed binding analysis between purified long and short forms of langerin and a series of KS disaccharide components. We also chemically synthesized oligomeric derivatives of L4 to develop a new high-affinity ligand of langerin. Results: We show that the binding critically requires the 6-sulfation of Gal and that the long form of langerin displays higher affinity than the short form. The synthesized trimeric (also designated as triangle or Tri) and polymeric (pendant) L4 derivatives displayed over 1000-fold higher affinity toward langerin than monomeric L4. The pendant L4, but not the L4 monomer, was found to effectively transduce langerin signaling in a model cell system. Conclusions: L4 is a specific ligand for langerin. Oligomerization of L4 unit increased the affinity toward langerin. General significance: These results suggest that oligomeric L4 derivatives will be useful for clarifying the langerin functions and for the development of new glycan-based anti-inflammatory drugs.

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