Abstract
Dectin-2, a C-type lectin on macrophages and other cells of the innate immune system, functions in response to pathogens, particularly fungi. The carbohydrate-recognition domain (CRD) in dectin-2 is linked to a transmembrane sequence that interacts with the common Fc receptor γ subunit to initiate immune signaling. The molecular mechanism by which dectin-2 selectively binds to pathogens has been investigated by characterizing the CRD expressed in a bacterial system. Competition binding studies indicated that the CRD binds to monosaccharides with modest affinity and that affinity was greatly enhanced for mannose-linked α1–2 or α1–4 to a second mannose residue. Glycan array analysis confirmed selective binding of the CRD to glycans that contain Manα1–2Man epitopes. Crystals of the CRD in complex with a mammalian-type high-mannose Man9GlcNAc2 oligosaccharide exhibited interaction with Manα1–2Man on two different termini of the glycan, with the reducing-end mannose residue ligated to Ca2+ in a primary binding site and the nonreducing terminal mannose residue occupying an adjacent secondary site. Comparison of the binding sites in DC-SIGN and langerin, two other pathogen-binding receptors of the innate immune system, revealed why these two binding sites accommodate only terminal Manα1–2Man structures, whereas dectin-2 can bind Manα1–2Man in internal positions in mannans and other polysaccharides. The specificity and geometry of the dectin-2-binding site provide the molecular mechanism for binding of dectin-2 to fungal mannans and also to bacterial lipopolysaccharides, capsular polysaccharides, and lipoarabinomannans that contain the Manα1–2Man disaccharide unit.
Highlights
Dectin-2, a C-type lectin on macrophages and other cells of the innate immune system, functions in response to pathogens, fungi
The carbohydrate-recognition domain (CRD) in dectin-2 is linked to a transmembrane sequence that interacts with the common Fc receptor ␥ subunit to initiate immune signaling
The sequences of CRDs in receptors that associate with the FcR␥ subunit form a closely related cluster (Fig. 1A) [17]
Summary
The sequences of CRDs in receptors that associate with the FcR␥ subunit form a closely related cluster (Fig. 1A) [17]. In addition to this set of interactions, which are common to most C-type CRDs that bind mannose and related sugars, C4 and C6 of mannose in the primary binding site make van der Waals contacts with Trp-182 (Fig. 6, B and C). Either mannose residue of Man␣1– 6Man could bind, but the positions of the 1- and 6-OH groups of the mannose residue in the primary
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