Biochemical and biophysical characterization of natural polyreactivity in antibodies.

Autor:	Borowska MT; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA., Boughter CT; Graduate Program in Biophysical Sciences, University of Chicago, Chicago, IL 60637, USA., Bunker JJ; Committee on Immunology, University of Chicago, Chicago, IL 60637, USA; Department of Pathology, University of Chicago, Chicago, IL 60637, USA., Guthmiller JJ; Department of Medicine, Section of Rheumatology, University of Chicago, Chicago, IL 60637, USA., Wilson PC; Committee on Immunology, University of Chicago, Chicago, IL 60637, USA; Department of Medicine, Section of Rheumatology, University of Chicago, Chicago, IL 60637, USA., Roux B; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA., Bendelac A; Committee on Immunology, University of Chicago, Chicago, IL 60637, USA; Department of Pathology, University of Chicago, Chicago, IL 60637, USA., Adams EJ; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA; Committee on Immunology, University of Chicago, Chicago, IL 60637, USA. Electronic address: ejadams@uchicago.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2023 Oct 31; Vol. 42 (10), pp. 113190. Date of Electronic Publication: 2023 Oct 05.
DOI:	10.1016/j.celrep.2023.113190
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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