The structural analysis of shark IgNAR antibodies reveals evolutionary principles of immunoglobulins
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Sharks and other cartilaginous fish are the phylogenetically oldest living organisms that rely on antibodies as part of their adaptive immune system. They produce the immunoglobulin new antigen receptor (IgNAR), a homodimeric heavy chain-only antibody, as a major part of their humoral adaptive immune response. Here, we report the atomic resolution structure of the IgNAR constant domains and a structural model of this heavy chain-only antibody. We find that despite low sequence conservation, the basic Ig fold of modern antibodies is already present in the evolutionary ancient shark IgNAR domains, highlighting key structural determinants of the ubiquitous Ig fold. In contrast, structural differences between human and shark antibody domains explain the high stability of several IgNAR domains and allowed us to engineer human antibodies for increased stability and secretion efficiency. We identified two constant domains, C1 and C3, that act as dimerization modules within IgNAR. Together with the individual domain structures and small-angle X-ray scattering, this allowed us to develop a structural model of the complete IgNAR molecule. Its constant region exhibits an elongated shape with flexibility and a characteristic kink in the middle. Despite the lack of a canonical hinge region, the variable domains are spaced appropriately wide for binding to multiple antigens. Thus, the shark IgNAR domains already display the well-known Ig fold, but apart from that, this heavy chain-only antibody employs unique ways for dimerization and positioning of functional modules.
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Nanobodies are naturally occurring H chain only antibodies in camelids and sharks.
“One of the most promising is the H chain only antibody, or nanobody that are naturally occurring in camelids (llamas, alpacas and camels) [27] and sharks [228, 229] (reviewed by Muyldermans [230] and Bannas et al. [27]).”
From Computational approaches to therapeutic antibody design: established methods and emerging trends (2020) · cites this paper as [228]
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Cas9-Based Local Enrichment and Genomics Sequence Revision of Megabase-Sized Shark IgNAR Loci
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- Authors
- Feige, M. J., Gräwert, M. A., Marcinowski, M., Hennig, J., Behnke, J., Ausländer, D., Herold, E. M., Peschek, J., Castro, C. D., Flajnik, M., Hendershot, L. M., Sattler, M., Groll, M., & Buchner, J.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Center for Integrated Protein Science Munich (DE)
- University of Maryland, Baltimore (US)
- Center for Integrated Protein Science Munich, Department Chemie, Technische Universität München, 85747 Garching, Germany;
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-05-15
- Volume
- 111
- Issue
- 22
- Pages
- 8155-8160
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4050542
- OpenAlex
- W2083986573
- Cited by
- 91
- References
- 51
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 11 · 2023: 9 · 2022: 9 · 2021: 13 · 2020: 5 · 2019: 5 · 2018: 7 · 2017: 5 · 2016: 4 · 2015: 8 · 2014: 2
- FWCI
- 4.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion)
- ERef Bayreuth (University of Bayreuth) (submittedVersion)
- Site cant be reached (submittedVersion, cc-by)
- Funders
- National Institutes of Health (R01OD010549)
- National Cancer Institute (Y1-CO-1020, P30CA021765)
- National Institute of General Medical Sciences (R01 GM54068, R01GM054068, Y1-GM-1104)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- heavy-chain antibodies, antibody evolution, constant domains, antibody dimerization, antibody stability, immunoglobulin secretion, structural model
- MeSH terms
- Amino Acid Sequence, Animals, Antibodies, Cells, Cultured, Humans, Immunoglobulin Constant Regions, Immunoglobulin Heavy Chains, Insecta, Molecular Sequence Data, Receptors, Antigen, Sharks, Urea, Protein Engineering, Protein Structure, Tertiary, Protein Folding, Evolution, Molecular, Protein Stability, Adaptive Immunity, Osmoregulation
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