Chain-length-selective cooperative assembly underlies β-glucan recognition by Dectin-1.

Abstract

Lectin receptors recognize specific glycan features within heterogeneous glycan populations to initiate immune signaling, yet how defined signals are extracted from structurally diverse ligand mixtures remains poorly understood. Here we report the molecular basis by which the innate immune receptor Dectin-1 recognizes the soluble β-glucan laminarin. Native mass spectrometry revealed that laminarin exists as heterogeneous chains spanning a degree of polymerization (DP) of 22-44, while Dectin-1 is strictly monomeric in solution. Isotopic mass tagging with uniformly ¹³C-labeled Dectin-1 established a preferred 3:3 receptor-to-laminarin stoichiometry (~80-85 kDa). Flow-induced dispersion analysis demonstrated cooperative binding with an apparent dissociation constant of 46 μM and a Hill coefficient of ~3, accompanied by a large increase in hydrodynamic radius. Analysis of the bound ligand fraction revealed selective enrichment of chains with DP 25-36, defining a preferred chain-length window. High-speed atomic force microscopy showed that individual Dectin-1 molecules undergo cooperative clustering on both laminarin and the longer β-glucan scleroglucan, while chemical crosslinking provided independent evidence for ligand-induced receptor association. Together, these findings demonstrate that β-glucan recognition by Dectin-1 is governed by chain-length selectivity and cooperative receptor assembly, consistent with a molecular ruler mechanism in which lectin receptors extract specific biological information from heterogeneous glycan populations.

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