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J Biol Chem. 2017 Aug 11;292(32):13402-13414. doi: 10.1074/jbc.M117.799080. Epub 2017 Jun 26.

Mechanism of pathogen recognition by human dectin-2.

Author information

1
From the Departments of Structural Biology and Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305 and.
2
the Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom.
3
the Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom maureen.taylor@imperial.ac.uk.

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.

KEYWORDS:

CLEC6A; carbohydrate-binding protein; glycobiology; lectin; macrophage; protein structure

PMID:
28652405
PMCID:
PMC5555199
DOI:
10.1074/jbc.M117.799080
[Indexed for MEDLINE]
Free PMC Article

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