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, Sho Yamasaki, Naoyuki Taniguchi

Research output: Contribution to journalArticle

4 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
JournalBiochimica et Biophysica Acta - General Subjects
DOIs
Publication statusAccepted/In press - 2018 Jan 1

Fingerprint

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

Keywords

  • C-type lectin
  • Chronic obstructive pulmonary disease (COPD)
  • Glycobiology
  • Keratan sulfate
  • L4
  • Langerin

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

Cite this

Ota, F., Hirayama, T., Kizuka, Y., Yamaguchi, Y., Fujinawa, R., Nagata, M., ... Taniguchi, N. (Accepted/In press). High affinity sugar ligands of C-type lectin receptor langerin. Biochimica et Biophysica Acta - General Subjects. 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, Sho; Taniguchi, Naoyuki.

In: Biochimica et Biophysica Acta - General Subjects, 01.01.2018.

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. 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, Sho ; Taniguchi, Naoyuki. / High affinity sugar ligands of C-type lectin receptor langerin. In: Biochimica et Biophysica Acta - General Subjects. 2018.
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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, Sho

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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KW - C-type lectin

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KW - Keratan sulfate

KW - L4

KW - Langerin

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