Mechanism of pathogen recognition by human dectin-2.

Area of Science:

• Immunology
• Structural Biology
• Glycobiology

Background:

• Dectin-2 is a C-type lectin receptor on innate immune cells, vital for pathogen recognition, particularly fungi.
• Its carbohydrate-recognition domain (CRD) initiates immune signaling upon pathogen binding via interaction with the Fc receptor γ subunit.
• Understanding dectin-2's selective pathogen binding mechanism is critical for innate immunity research.

Purpose of the Study:

• To elucidate the molecular mechanism of dectin-2's selective binding to pathogen-associated carbohydrates.
• To characterize the binding properties and structural basis of dectin-2's carbohydrate recognition domain (CRD).

Main Methods:

• Expressed and purified dectin-2 CRD in a bacterial system.
• Performed competition binding assays with monosaccharides and defined mannose structures.
• Utilized glycan array analysis to identify preferred glycan epitopes.
• Determined crystal structures of the dectin-2 CRD in complex with a high-mannose oligosaccharide.

Main Results:

• Dectin-2 CRD exhibits modest affinity for monosaccharides, with significantly enhanced binding to mannose linked α1-2 or α1-4 to a second mannose.
• Glycan array confirmed selective binding to Manα1-2Man epitopes.
• Crystal structures revealed dectin-2 binds Manα1-2Man at two termini of a high-mannose glycan, with a Ca2+-ligated primary site and a secondary site.
• Compared to DC-SIGN and langerin, dectin-2 accommodates internal Manα1-2Man, enabling binding to diverse polysaccharides like fungal mannans and bacterial lipopolysaccharides.

Conclusions:

• The unique specificity and geometry of the dectin-2 binding site explain its ability to recognize Manα1-2Man structures in various positions within polysaccharides.
• This mechanism underlies dectin-2's role in binding fungal mannans, bacterial lipopolysaccharides, and other glycans containing the Manα1-2Man disaccharide unit.
• Findings provide molecular insight into dectin-2's function in innate immunity and host defense.