James Crowe
Faculty Member
Last active: 3/31/2020

Structural basis for norovirus neutralization by an HBGA blocking human IgA antibody.

Shanker S, Czakó R, Sapparapu G, Alvarado G, Viskovska M, Sankaran B, Atmar RL, Crowe JE, Estes MK, Prasad BV
Proc Natl Acad Sci U S A. 2016 113 (40): E5830-E5837

PMID: 27647885 · PMCID: PMC5056091 · DOI:10.1073/pnas.1609990113

Human noroviruses (HuNoVs) cause sporadic and epidemic gastroenteritis worldwide. They are classified into two major genogroups (GI and GII), with each genogroup further divided into multiple genotypes. Susceptibility to these viruses is influenced by genetically determined histo-blood group antigen (HBGA) expression. HBGAs function as cell attachment factors by binding to a surface-exposed region in the protruding (P) domain of the capsid protein. Sequence variations in this region that result in differential HBGA binding patterns and antigenicity are suggested to form a basis for strain diversification. Recent studies show that serum antibodies that block HBGA binding correlate with protection against illness. Although genogroup-dependent variation in HBGA binding specificity is structurally well characterized, an understanding of how antibodies block HBGA binding and how genotypic variations affect such blockade is lacking. Our crystallographic studies of the GI.1 P domain in complex with the Fab fragment of a human IgA monoclonal antibody (IgA 5I2) with HBGA blocking activity show that the antibody recognizes a conformational epitope formed by two surface-exposed loop clusters in the P domain. The antibody engulfs the HBGA binding site but does not affect its structural integrity. An unusual feature of the antigen recognition by IgA 5I2 is the predominant involvement of the CDR light chain 1 in contrast to the commonly observed CDR heavy chain 3, providing a unique perspective into antibody diversity in antigen recognition. Identification of the antigenic site in the P domain shows how genotypic variations might allow escape from antibody neutralization and exemplifies the interplay between antigenicity and HBGA specificity in HuNoV evolution.

MeSH Terms (15)

Amino Acid Sequence Antibodies, Blocking Antigens Blood Group Antigens Crystallography, X-Ray Epitopes Genotype Humans Immunoglobulin A Immunoglobulin Fab Fragments Models, Molecular Neutralization Tests Norovirus Protein Domains Viral Proteins

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