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

• Published in: The Journal of pharmacology and experimental therapeutics 2008-04, Vol.325 (1), p.115-123
• Main Authors: Adams, Elizabeth L, Rice, Peter J, Graves, Bridget, Ensley, Harry E, Yu, Hai, Brown, Gordon D, Gordon, Siamon, Monteiro, Mario A, Papp-Szabo, Erzsebet, Lowman, Douglas W, Power, Trevor D, Wempe, Michael F, Williams, David L
• Format: Article
• Language: English
• Subjects: Animals; beta-Glucans - chemistry; beta-Glucans - metabolism; Carbohydrate Conformation; Cell Line; Humans; Immunity, Innate; Lectins, C-Type; Ligands; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mitosporic Fungi - chemistry; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Protein Binding; Substrate Specificity; Transfection; Yeasts - chemistry
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.107.133124

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.