Structural integrity of antigen receptors 2259926

Abstract Introduction Antibodies play a pivotal role in the adaptive immune system due to their ability to bind pathogens and toxins. There are two functionally similar, but structurally diverse antibodies that have arisen throughout evolution. Immunoglobulin (Ig)-based antibodies are found in jawed vertebrates, like humans; and variable lymphocyte receptors (VLRs), which are leucine rich repeats (LRRs)-based antibodies found in jawless vertebrates, like lampreys. While a broad baseline diversity is generated in both Ig-based and LRR-based antibodies, an additional form of antibody diversification—somatic hypermutation (SHM)--is unique to Ig-based antibodies. To date, there has been no solid evidence of SHM in lamprey LRR-based antibodies despite having genes that possess the enzymatic machinery to do so. This opens doors to evaluate possible differences in the negative structural impact somatic mutations would have on Ig- and LRR-based antibodies. Methods We will test this hypothesis by determining the SHM-like mutational tolerance of Ig-based and LRR-based antigen receptors in vitro, and defining diversity and maturation of Ig and VLR substrates in vivo. Results Preliminary computational data suggest that the diverse structures of Ig- and LRR-based antibodies vary in their capacity to maintain structural integrity during hypermutation, a process crucial for the expression of antibody diversity. Conclusion These results are consistent with a hypothesis that structural stability constraints may play a role in real-time protein mutability potential and that Ig-based antibodies are able to express greater real-time diversity than LRR-based antibodies. This will deliver biophysical insights into the aptitude of evolutionarily distinct but functionally convergent adaptive immune receptors for mutation-driven diversification. Funding Source National Science Foundation Graduate Research Fellowship Program (NSF GRFP) DGE 2140743, Ruth L. Kirschstein Predoctoral Individual National Research Service Award (NIH F31) 1F31AI186232, FujiFilm Fellowship Topic Categories Veterinary and Comparative Immunology (VET)