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.
Division of Health Sciences and Nutrition, Commonwealth Scientific and Industrial Research Organization, and Cooperative Research Centre for Diagnostics, 343 Royal Parade, Parkville 3052, Australia.
V A
VA
Streltsov
J N
JN
Varghese
J A
JA
Carmichael
R A
RA
Irving
P J
PJ
Hudson
S D
SD
Nuttall
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