Adaption of human antibody λ and κ light chain architectures to CDR repertoires

Author:

van der Kant Rob12ORCID,Bauer Joschka3,Karow-Zwick Anne R3,Kube Sebastian3,Garidel Patrick3,Blech Michaela3,Rousseau Frederic12,Schymkowitz Joost12ORCID

Affiliation:

1. Switch Laboratory, VIB Center for Brain and Disease Research, Herestraat 49, Leuven, Belgium

2. Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49 Box, B-3000 Leuven, Belgium

3. Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach/Riss, Germany

Abstract

Abstract Monoclonal antibodies bind with high specificity to a wide range of diverse antigens, primarily mediated by their hypervariable complementarity determining regions (CDRs). The defined antigen binding loops are supported by the structurally conserved β-sandwich framework of the light chain (LC) and heavy chain (HC) variable regions. The LC genes are encoded by two separate loci, subdividing the entity of antibodies into kappa (LCκ) and lambda (LCλ) isotypes that exhibit distinct sequence and conformational preferences. In this work, a diverse set of techniques were employed including machine learning, force field analysis, statistical coupling analysis and mutual information analysis of a non-redundant antibody structure collection. Thereby, it was revealed how subtle changes between the structures of LCκ and LCλ isotypes increase the diversity of antibodies, extending the predetermined restrictions of the general antibody fold and expanding the diversity of antigen binding. Interestingly, it was found that the characteristic framework scaffolds of κ and λ are stabilized by diverse amino acid clusters that determine the interplay between the respective fold and the embedded CDR loops. In conclusion, this work reveals how antibodies use the remarkable plasticity of the beta-sandwich Ig fold to incorporate a large diversity of CDR loops.

Funder

VIB

University of Leuven

Funds for Scientific Research Flanders

Flanders Institute for Science and Technology

Federal Office for Scientific Affairs of Belgium

European Union’s Horizon 2020

Boehringer Ingelheim Pharma GmbH & Co

Publisher

Oxford University Press (OUP)

Subject

Molecular Biology,Biochemistry,Bioengineering,Biotechnology

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