Structural evidence for evolution of shark Ig new antigen receptor variable domain antibodies from a cell-surface receptor.
The Ig new antigen receptors (IgNARs) are single-domain antibodies found in the serum of sharks. Here, we report 2.2- and 2.8-A 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 beta-hairpin structure, suggesting a distinct selective advantage in accessing cryptic antigenic epitopes.
Streltsov
V A
VA
Division of Health Sciences and Nutrition, Commonwealth Scientific and Industrial Research Organization, and Cooperative Research Centre for Diagnostics, 343 Royal Parade, Parkville 3052, Australia.
Varghese
J N
JN
Carmichael
J A
JA
Irving
R A
RA
Hudson
P J
PJ
Nuttall
S D
SD
D000818:Animals; D000906:Antibodies / Q000737:chemistry* / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000737:chemistry; D018360:Crystallography, X-Ray; D019281:Dimerization; D019143:Evolution, Molecular; D007135:Immunoglobulin Variable Region / Q000737:chemistry* / Q000235:genetics; D008958:Models, Molecular; D008968:Molecular Conformation; D020836:Protein Structure, Quaternary; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics; D011946:Receptors, Antigen / Q000737:chemistry* / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry; D012754:Sharks / Q000276:immunology*
D000906:Antibodies; D015815:Cell Adhesion Molecules; D007135:Immunoglobulin Variable Region; D021122:Protein Subunits; D011946:Receptors, Antigen; D011948:Receptors, Antigen, T-Cell