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

Liz Adams, Peter 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, David L Williams

Research output: Contribution to journalArticle

171 Citations (Scopus)

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)-beta/(1-->6)-beta-glucans as well as nonglucan polymers. Dectin-1 is highly specific for glucans with a pure (1-->3)-beta-linked backbone structure. Although Dectin-1 is highly specific for (1-->3)-beta-d-glucans, it does not recognize all glucans equally. Dectin-1 differentially interacted with (1-->3)-beta-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)-beta 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.
Original languageEnglish
Pages (from-to)115-123
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume325
Issue number1
Early online date2 Jan 2008
DOIs
Publication statusPublished - Apr 2008

Keywords

  • Animals
  • Carbohydrate Conformation
  • Cell Line
  • Humans
  • Immunity, Innate
  • Ligands
  • Membrane Proteins
  • Mice
  • Mitosporic Fungi
  • Nerve Tissue Proteins
  • Protein Binding
  • Substrate Specificity
  • Transfection
  • Yeasts
  • beta-Glucans

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  • Cite this

    Adams, L., Rice, P., Graves, B., Ensley, H. E., Yu, H., Brown, G. D., Gordon, S., Monteiro, M. A., Papp-Szabo, E., Lowman, D. W., Power, T. D., Wempe, M. F., & Williams, D. L. (2008). 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. Journal of Pharmacology and Experimental Therapeutics, 325(1), 115-123. https://doi.org/10.1124/jpet.107.133124