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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Differential High-Affinity Interaction of Dectin-1 with Natural or Synthetic Glucans Is Dependent upon Primary Structure and Is Influenced by Polymer Chain Length and Side-Chain Branching

Elizabeth L. Adams, Peter J. Rice, Bridget Graves, Harry E. Ensley, Hai Yu, Gordon D. Brown, Siamon Gordon, Mario A. Monteiro, Erzsebet Papp-Szabo, Douglas W. Lowman, Trevor D. Power, Michael F. Wempe and David L. Williams
Journal of Pharmacology and Experimental Therapeutics April 2008, 325 (1) 115-123; DOI: https://doi.org/10.1124/jpet.107.133124
Elizabeth L. Adams
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Peter J. Rice
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Bridget Graves
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Harry E. Ensley
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Hai Yu
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Gordon D. Brown
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Siamon Gordon
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Mario A. Monteiro
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Erzsebet Papp-Szabo
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Douglas W. Lowman
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Trevor D. Power
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Michael F. Wempe
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David L. Williams
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Abstract

Glucans are structurally diverse fungal biopolymers that stimulate innate immunity and are fungal pathogen-associated molecular patterns. Dectin-1 is a C-type lectin-like pattern recognition receptor that binds glucans and induces innate immune responses to fungal pathogens. We examined the effect of glucan structure on recognition and binding by murine recombinant Dectin-1 with a library of natural product and synthetic (1→3)-β/(1→6)-β-glucans as well as nonglucan polymers. Dectin-1 is highly specific for glucans with a pure (1→3)-β-linked backbone structure. Although Dectin-1 is highly specific for (1→3)-β-d-glucans, it does not recognize all glucans equally. Dectin-1 differentially interacted with (1→3)-β-d-glucans over a very wide range of binding affinities (2.6 mM–2.2 pM). One of the most striking observations that emerged from this study was the remarkable high-affinity interaction of Dectin-1 with certain glucans (2.2 pM). These data also demonstrated that synthetic glucan ligands interact with Dectin-1 and that binding affinity increased in synthetic glucans containing a single glucose side-chain branch. We also observed differential recognition of glucans derived from saprophytes and pathogens. We found that glucan derived from a saprophytic yeast was recognized with higher affinity than glucan derived from the pathogen Candida albicans. Structural analysis demonstrated that glucan backbone chain length and (1→6)-β side-chain branching strongly influenced Dectin-1 binding affinity. These data demonstrate: 1) the specificity of Dectin-1 for glucans; 2) that Dectin-1 differentiates between glucan ligands based on structural determinants; and 3) that Dectin-1 can recognize and interact with both natural product and synthetic glucan ligands.

Footnotes

  • This work was supported, in part, by Public Health Service Grant GM53522 from the National Institute of General Medical Sciences (to D.L.W.) and National Sciences and Engineering Research Council of Canada (to M.A.M.).

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.107.133124.

  • ABBREVIATIONS: PAMP, pathogen-associated molecular pattern; PRR, pattern recognition receptor; AGRU, anhydroglucose repeat unit; NMR, nuclear magnetic resonance; NIS/AgOTf; N-iodosuccinimide/silver trifluoromethanesulfonate; DMSO, dimethyl sulfoxide; RMS, root mean square radius; GPC/MALLS, gel permeation chromatography/multiangle laser light scattering detection; DAP, diaminopropane; RU, resonance units; CPU, central processing unit; CI, confidence interval.

  • ↵ Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 371 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 371, Issue 3
1 Dec 2019
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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Differential High-Affinity Interaction of Dectin-1 with Natural or Synthetic Glucans Is Dependent upon Primary Structure and Is Influenced by Polymer Chain Length and Side-Chain Branching

Elizabeth L. Adams, Peter J. Rice, Bridget Graves, Harry E. Ensley, Hai Yu, Gordon D. Brown, Siamon Gordon, Mario A. Monteiro, Erzsebet Papp-Szabo, Douglas W. Lowman, Trevor D. Power, Michael F. Wempe and David L. Williams
Journal of Pharmacology and Experimental Therapeutics April 1, 2008, 325 (1) 115-123; DOI: https://doi.org/10.1124/jpet.107.133124

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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Differential High-Affinity Interaction of Dectin-1 with Natural or Synthetic Glucans Is Dependent upon Primary Structure and Is Influenced by Polymer Chain Length and Side-Chain Branching

Elizabeth L. Adams, Peter J. Rice, Bridget Graves, Harry E. Ensley, Hai Yu, Gordon D. Brown, Siamon Gordon, Mario A. Monteiro, Erzsebet Papp-Szabo, Douglas W. Lowman, Trevor D. Power, Michael F. Wempe and David L. Williams
Journal of Pharmacology and Experimental Therapeutics April 1, 2008, 325 (1) 115-123; DOI: https://doi.org/10.1124/jpet.107.133124
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