Structural and thermodynamic insights into antibody light chain tetramer formation through 3D domain swapping

Takahiro Sakai, Tsuyoshi Mashima, Naoya Kobayashi, Hideaki Ogata, Lian Duan, Ryo Fujiki, Kowit Hengphasatporn, Taizo Uda, Yasuteru Shigeta, Emi Hifumi and Shun Hirota ()
Additional contact information
Takahiro Sakai: Division of Materials Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, 8916-5 Takayama
Tsuyoshi Mashima: Division of Materials Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, 8916-5 Takayama
Naoya Kobayashi: Division of Materials Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, 8916-5 Takayama
Hideaki Ogata: University of Hyogo, 3-2-1 Koto, Kamigori-cho
Lian Duan: University of Tsukuba, 1-1-1 Tennodai
Ryo Fujiki: University of Tsukuba, 1-1-1 Tennodai
Kowit Hengphasatporn: University of Tsukuba, 1-1-1 Tennodai
Taizo Uda: Nanotechnology Laboratory, Institute of Systems, Information Technologies and Nanotechnologies (ISIT), 4‑1 Kyudai‑Shinmachi
Yasuteru Shigeta: University of Tsukuba, 1-1-1 Tennodai
Emi Hifumi: Oita University, 700 Dannoharu
Shun Hirota: Division of Materials Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, 8916-5 Takayama

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Overexpression of antibody light chains in small plasma cell clones can lead to misfolding and aggregation. On the other hand, the formation of amyloid fibrils from antibody light chains is related to amyloidosis. Although aggregation of antibody light chain is an important issue, atomic-level structural examinations of antibody light chain aggregates are sparse. In this study, we present an antibody light chain that maintains an equilibrium between its monomeric and tetrameric states. According to data from X-ray crystallography, thermodynamic and kinetic measurements, as well as theoretical studies, this antibody light chain engages in 3D domain swapping within its variable region. Here, a pair of domain-swapped dimers creates a tetramer through hydrophobic interactions, facilitating the revelation of the domain-swapped structure. The negative cotton effect linked to the β-sheet structure, observed around 215 nm in the circular dichroism (CD) spectrum of the tetrameric variable region, is more pronounced than that of the monomer. This suggests that the monomer contains less β-sheet structures and exhibits greater flexibility than the tetramer in solution. These findings not only clarify the domain-swapped structure of the antibody light chain but also contribute to controlling antibody quality and advancing the development of future molecular recognition agents and drugs.

Date: 2023
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DOI: 10.1038/s41467-023-43443-4

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