Location: Genetics and Animal BreedingTitle: Structural diversity of ultralong CDRH3s in seven bovine antibody heavy chains
|DONG, J - Vanderbilt University Medical Center
|FINN, JESSICA - Vanderbilt University Medical Center
|LARSEN, PETER - Former ARS Employee
|Smith, Timothy - Tim
|CROWE, JAMES - Vanderbilt University Medical Center
Submitted to: Frontiers in Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/1/2019
Publication Date: 3/22/2019
Citation: Dong, J., Finn, J.A., Larsen, P.A., Smith, T.P.L., Crowe, J.E. 2019. Structural diversity of ultralong CDRH3s in seven bovine antibody heavy chains. Frontiers in Immunology. 10:558. https://doi.org/10.3389/fimmu.2019.00558.
Interpretive Summary: Cattle have a unique way of generating antibodies that protect against infection by bacteria and viruses. In contrast to humans or mice, which use a large number of antibody-related genes that are shuffled within each immune cell to create a diverse set of antibodies capable of recognizing invaders, cattle use a much smaller number of genes and use an error-prone shuffling mechanism that introduces diversity that is not encoded in the progenitor cell DNA. One part of this diversification is the presence of pathogen-binding sites on the antibody that are much longer than those found in human or mouse antibodies. This study uses physical methods to look at the 3-dimensional structure of the long antibodies to probe details of how they work, which may lead to a better understanding of the immune process in both cattle and humans.
Technical Abstract: Antigen recognition by mammalian antibodies represents the most diverse setting for protein-protein interactions because antibody variable regions contain exceptionally diverse variable gene repertoires of DNA sequences containing combinatorial, non-templated junctional mutational diversity. Some animals use additional strategies to achieve structural complexity in the antibody combining site, and one of the most interesting of these is the formation of ultralong heavy chain complementarity determining region 3 loops in cattle. Repertoire sequencing studies of bovine antibody heavy chain variable sequences revealed that bovine antibodies can contain heavy chain complementarity determining region 3 (CDRH3) loops with 60 or more amino acids, with complex structures stabilized by multiple disulfide bonds. It is clear that bovine antibodies can achieve long, peculiarly structured CDR3s, but the range of diversity and complexity of those structures is poorly understood. We determined the atomic resolution structure of seven ultralong bovine CDRH3 loops. The studies, combined with five previous structures, reveal a large diversity of cysteine pairing variations, and highly diverse globular domains.