Structural Evidence for Evolution of Shark Ig New Antigen Receptor Variable Domain Antibodies from a Cell-Surface Receptor

• Published in: Proceedings of the National Academy of Sciences - PNAS 2004-08, Vol.101 (34), p.12444-12449
• Main Authors: Streltsov, V. A., Varghese, J. N., Carmichael, J. A., Irving, R. A., Hudson, P. J., Nuttall, S. D., Springer, Timothy A.
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antibodies - chemistry; Antibodies - genetics; Antigens; Biochemistry; Biological Sciences; Cell adhesion molecules; Cell Adhesion Molecules - chemistry; Crystallography, X-Ray; Crystals; Dimerization; Dimers; Disulfides; Evolution, Molecular; Immunoglobulin Variable Region - chemistry; Immunoglobulin Variable Region - genetics; Immunoglobulins; Models, Molecular; Molecular chains; Molecular Conformation; Molecules; Protein Structure, Quaternary; Protein Subunits - chemistry; Protein Subunits - genetics; Receptors; Receptors, Antigen - chemistry; Receptors, Antigen - genetics; Receptors, Antigen, T-Cell - chemistry; Sharks; Sharks - immunology; T cell receptors; Topology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0403509101

The Ig new antigen receptors (IgNARs) are single-domain antibodies found in the serum of sharks. Here, we report 2.2- and 2.8-Å structures of the type 2 IgNAR variable domains 12Y-1 and 12Y-2. Structural features include, first, an Ig superfamily topology transitional between cell adhesion molecules, antibodies, and T cell receptors; and, second, a vestigial complementarity-determining region 2 at the "bottom" of the molecule, apparently discontinuous from the antigen-binding paratope and similar to that observed in cell adhesion molecules. Thus, we suggest that IgNARs originated as cell-surface adhesion molecules coopted to the immune repertoire and represent an evolutionary lineage independent of variable heavy chain/variable light chain type antibodies. Additionally, both 12Y-1 and 12Y-2 form unique crystallographic dimers, predominantly mediated by main-chain framework interactions, which represent a possible model for primordial cell-based interactions. Unusually, the 12Y-2 complementarity-determining region 3 also adopts an extended β-hairpin structure, suggesting a distinct selective advantage in accessing cryptic antigenic epitopes.