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Cited by 9Protein Structure and DynamicsMonoclonal and Polyclonal Antibodies ResearchProtein purification and stability

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

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Sakai, Takahiro, Mashima, Tsuyoshi, Kobayashi, Naoya, Ogata, Hideaki, Duan, Lian, Fujiki, Ryo, Hengphasatporn, Kowit, Uda, Taizo, Shigeta, Yasuteru, Hifumi, Emi, Hirota, Shun·2023·Nature Communications
DOI 10.1038/s41467-023-43443-4PMC PMC10709643

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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.

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Metadata

Authors
Sakai, T., Mashima, T., Kobayashi, N., Ogata, H., Duan, L., Fujiki, R., Hengphasatporn, K., Uda, T., Shigeta, Y., Hifumi, E., & Hirota, S.
Affiliations
  • Nara Institute of Science and Technology (JP)
  • University of Hyogo (JP)
  • University of Tsukuba (JP)
  • Institute of Systems, Information Technologies and Nanotechnologies (JP)
  • Oita University (JP)
Corresponding author
Hirota, Shun
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-12-08
Volume
14
Issue
1
Pages
7807-7807
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-023-43443-4
PMC
PMC10709643
OpenAlex
W4389481063
Cited by
9
References
3
Citations by year
2026: 2 · 2025: 3 · 2024: 4
FWCI
0.80
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • MEXT | JST | Core Research for Evolutional Science and Technology (JP20338388)
  • MEXT | Japan Society for the Promotion of Science (JP26288080, 23H04879)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
Keywords
antibody light chain, tetramer formation, protein aggregation, amyloid fibrils, amyloidosis, plasma cell clone, hydrophobic interactions, beta-sheet, circular dichroism, protein folding thermodynamics, protein flexibility, antibody quality control
MeSH terms
Amyloid, Amyloidosis, Humans, Immunoglobulin Light Chains, Thermodynamics, Crystallography, X-Ray

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