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Histo-Blood Group Antigen Presentation Is Critical for Binding of Norovirus VLP to Glycosphingolipids in Model Membranes

Artikel i vetenskaplig tidskrift
Författare Waqas Nasir
M. Frank
A. Kunze
M. Bally
F. Parra
Per-Georg Nyholm
F. Hook
Göran Larson
Publicerad i Acs Chemical Biology
Volym 12
Nummer/häfte 5
Sidor 1288-1296
ISSN 1554-8929
Publiceringsår 2017
Publicerad vid Institutionen för biomedicin, avdelningen för klinisk kemi och transfusionsmedicin
Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi
Sidor 1288-1296
Språk en
Länkar doi.org/10.1021/acschembio.7b00152
Ämnesord molecular-dynamics simulations, epithelial-cells, glycolipid receptors, small-intestine, secretor fut2, abo-phenotype, group-a, virus, surface, lewis, Biochemistry & Molecular Biology
Ämneskategorier Medicinsk bioteknologi

Sammanfattning

Virus entry depends on biomolecular recognition at the surface of cell membranes. In the case of glycolipid receptors, these events are expected to be influenced by how the glycan epitope close to the membrane is presented to the virus. This presentation of membrane associated glycans is more restricted than that of glycans in solution, particularly because of orientational constraints imposed on the glycolipid through its lateral interactions with other membrane lipids and proteins. We have developed and employed a total internal reflection fluorescence microscopy-based binding assay and. a scheme for molecular dynamics (MD) membrane simulations to investigate the consequences of various glycan presentation effects. The system studied was histo-blood group antigen (HBGA) epitopes of membrane-bound glycosphingolipids (GSLs) derived from small intestinal epithelium of humans (type 1 chain) and dogs (type 2 chain) interacting with GII.4 norovirus-like particles. Our experimental results showed strong binding to all lipid-linked type 1 chain HBGAs but no or only weak binding to the corresponding type 2 chain HBGAs. This is in contrast to results derived from STD experiments with free HBGAs in solution where binding was observed for Lewis x. The MD data suggest that the strong binding to type 1 chain glycolipids was due to the well-exposed (1,2)-linked alpha-L-Fucp and (1,4)- linked alpha-L-Fucp residues, while the weaker binding or lack of binding to type 2 chain HBGAs was due to the very restricted accessibility of the (1,3) -linked alpha-L-Fucp residue when the glycolipid is embedded in a phospholipid membrane. Our results not only contribute to a general understanding of protein carbohydrate interactions on model membrane surfaces, particularly in the context of virus binding, but also suggest a possible role of human intestinal GSLs as potential receptors for norovirus uptake.

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