1. Biochemical and biophysical characterization of natural polyreactivity in antibodies.
- Author
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Borowska, Marta T., Boughter, Christopher T., Bunker, Jeffrey J., Guthmiller, Jenna J., Wilson, Patrick C., Roux, Benoit, Bendelac, Albert, and Adams, Erin J.
- Abstract
To become specialized binders, antibodies undergo a process called affinity maturation to maximize their binding affinity. Despite this process, some antibodies retain low-affinity binding to diverse epitopes in a phenomenon called polyreactivity. Here we seek to understand the molecular basis of this polyreactivity in antibodies. Our results highlight that polyreactive antigen-binding fragments (Fabs) bind their targets with low affinities, comparable to T cell receptor recognition of autologous classical major histocompatibility complex. Extensive mutagenic studies find no singular amino acid residue or biochemical property responsible for polyreactive interaction, suggesting that polyreactive antibodies use multiple strategies for engagement. Finally, our crystal structures and all-atom molecular dynamics simulations of polyreactive Fabs show increased rigidity compared to their monoreactive relatives, forming a neutral and accessible platform for diverse antigens to bind. Together, these data support a cooperative strategy of rigid neutrality in establishing the polyreactive status of an antibody molecule. [Display omitted] • Polyreactive antibodies show increased rigidity and neutrality in their binding surfaces • Polyreactive antibodies engage with low affinities akin to autologous TCR-MHC interactions Binding promiscuity is an inherent property of immune recognition, manifested in antibodies as polyreactivity. Borowska et al. dissect this phenomenon at the molecular level and show that the binding surfaces of polyreactive antibodies use increased rigidity and neutrality in ligand engagement. This provides a key mechanism for understanding polyreactivity in antibodies. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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