Journal Article

Unraveling the role of the secretor antigen in human rotavirus attachment to histo-blood group antigens

Yebra, María J., Vila-Vicent, Susana, Santiso-Bellón, Cristina, Buesa, Javier, Gozalbo-Rovira, Roberto, Marina, Alberto, Monedero, Vicente, Rodríguez-Díaz, Jesús, Ciges-Tomas, J. Rafael

2019

Overview

Rotavirus is the leading agent causing acute gastroenteritis in young children, with the P[8] genotype accounting for more than 80% of infections in humans. The molecular bases for binding of the VP8* domain from P[8] VP4 spike protein to its cellular receptor, the secretory H type-1 antigen (Fuc-α1,2-Gal-β1,3-GlcNAc; H1), and to its precursor lacto-N-biose (Gal-β1,3-GlcNAc; LNB) have been determined. The resolution of P[8] VP8* crystal structures in complex with H1 antigen and LNB and site-directed mutagenesis experiments revealed that both glycans bind to the P[8] VP8* protein through a binding pocket shared with other members of the P[II] genogroup (i.e.: P[4], P[6] and P[19]). Our results show that the L-fucose moiety from H1 only displays indirect contacts with P[8] VP8*. However, the induced conformational changes in the LNB moiety increase the ligand affinity by two-fold, as measured by surface plasmon resonance (SPR), providing a molecular explanation for the different susceptibility to rotavirus infection between secretor and non-secretor individuals. The unexpected interaction of P[8] VP8* with LNB, a building block of type-1 human milk oligosaccharides, resulted in inhibition of rotavirus infection, highlighting the role and possible application of this disaccharide as an antiviral. While key amino acids in the H1/LNB binding pocket were highly conserved in members of the P[II] genogroup, differences were found in ligand affinities among distinct P[8] genetic lineages. The variation in affinities were explained by subtle structural differences induced by amino acid changes in the vicinity of the binding pocket, providing a fine-tuning mechanism for glycan binding in P[8] rotavirus.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: ABO Blood-Group System - chemistry / Accounting / Affinity / Amino acid sequence / Amino acids / Analysis / Antigens / Antigens, Viral - chemistry / Antiviral agents / Binding / Binding Sites / Biology and life sciences / Blood groups / Breast milk / Capsid Proteins - chemistry / Cell Line / Child health / Children / Crystal structure / Crystallography / Crystallography, X-Ray / Disaccharides / Disease susceptibility / EDTA / Epithelium / Food science / Fucose / Funding / Gastroenteritis / Genetic diversity / Genotype & phenotype / Genotypes / Glycan / Health aspects / Humans / Immunology / Infection / Infections / Ligands / Medicine / Medicine and Health Sciences / Milk / Oligosaccharides / Physical Sciences / Polysaccharides / Protein binding / Proteins / Research and Analysis Methods / Risk factors / RNA-Binding Proteins - chemistry / Rotavirus / Rotavirus - chemistry / Rotavirus infections / Site-directed mutagenesis / Spike protein / Surface plasmon resonance / Viral Nonstructural Proteins - chemistry / Viruses