NMR studies of the specific interaction of dc-sign with the blood group a/b antigens

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Mini symposium: Glycobiology at the LUMC and beyond

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NMR studies of the specific interaction of dc-sign with the blood group a/b antigens

Pablo Valverde 1 , Ana Ardá 1 , Sandra Delgado 1 , José Daniel Martínez 1 , Jean-Baptiste Vendeville 2 , Bruno Linclau 2 , Javier Cañada 4 , Niels Christian-Reichard 3 , Jesús Jiménez-Barbero 1

1 CIC bioGUNE, Derio, Spain, 2 Chemistry, University of Southampton, Southampton, United Kingdom, 3 CIC biomaGUNE, San Sebastián, Spain, 4 CIB CSIC, Madrid, Spain

The DC-SIGN (dendritic cell-specific ICAM-3 grabbing non-integrin) protein is a key receptor of the C-type lectin receptor (CLR) family. This human lectin acts as a pathogen recognition receptor (PRR) through the specific interaction with complex oligosaccharides distributed on the pathogen surface, via its calcium-dependent binding site. At the same time, its role in the immune modulation and homeostasis has been also described by means of specific targeting of endogenous glycoproteins like ICAM-3.1

The broad specificity in binding is one particular feature of this lectin. Previous glycan array data2,3 agree with the existence of two main ligands for DCSIGN: L-fucose (Fuc) and D-mannose (Man). Fuc is commonly found at the terminal positions of Lewis-type and ABH-type antigens in mammalian cells, while Man is the major component of the highly branched oligosaccharides attached to membrane glycoproteins in different pathogens, as gp120 in HIV. In addition, these studies also speculated on how glycan presentation and subtle structural differences between similar Fuc- or Man-containing motifs might tune or modify the binding affinities4. In this regard, the interaction details at a molecular level, especially for the endogenous Fuc-containing partners, remain rather unexplored.

We have unraveled the key structural details of the molecular recognition event of the A- and B- histo blood group antigens by DC-SIGN. We have employed a variety of NMR methods assisted by molecular modeling protocols to define the binding features of these antigens to the carbohydrate recognition domain of DC-SIGN. This methodology has allowed us to propose a well-defined binding model for both blood groups. These results provide the initial milestones for forthcoming studies with other ligands, including longer and branched saccharides.

Proposed binding pose for the Blood Group B type VI tetrasaccharide interacting with DC-SIGN.

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