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Published online before print September 30, 2005, 10.1110/ps.051709505
Protein Science (2005), 14:2901-2909. Published by Cold Spring Harbor Laboratory Press. Copyright © 2005 The Protein Society
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PROTEIN STRUCTURE REPORT

Structure of a shark IgNAR antibody variable domain and modeling of an early-developmental isotype

Victor A. Streltsov, Jennifer A. Carmichael and Stewart D. Nuttall

Cooperative Research Centre for Diagnostics at CSIRO Molecular and Health Technologies, Parkville, Victoria 3052, Australia

(RECEIVED July 18, 2005; FINAL REVISION August 17, 2005; ACCEPTED August 22, 2005)

The new antigen receptor (IgNAR) antibodies from sharks are disulphide bonded dimers of two protein chains, each containing one variable and five constant domains. Three types of IgNAR variable domains have been discovered, with Type 3 appearing early in shark development and being overtaken by the antigen-driven affinity-matured Type 1 and 2 response. Here, we have determined the first structure of a naturally occurring Type 2 IgNAR variable domain, and identified the disulphide bond that links and stabilizes the CDR1 and CDR3 loops. This disulphide bridge locks the CDR3 loop in an "upright" conformation in contrast to other shark antibody structures, where a more lateral configuration is observed. Further, we sought to model the Type 3 isotype based on the crystallographic structure reported here. This modeling indicates (1) that internal Type 3-specific residues combine to pack into a compact immunoglobulin core that supports the CDR loop regions, and (2) that despite apparent low-sequence variability, there is sufficient plasticity in the CDR3 loop to form a conformationally diverse antigen-binding surface.

Keywords: immunoglobulin new antigen receptor; single variable domain; antibody; paratope; shark; cell adhesion molecule

Abbreviations: IgNAR, new antigen receptor antibody from sharks • VNAR, single variable domain of the IgNAR antibody • CDR, complementarity determining region • kDa, kilodalton

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.051709505.

Reprint requests to: Stewart D. Nuttall or Victor A. Streltsov, CSIRO Molecular and Health Technologies, 343 Royal Parade, Parkville, Victoria 3052, Australia; e-mail: Stewart.Nuttall{at}csiro.au or Victor.Streltsov{at}csiro.au; fax: +(61-3) 9662-7314.


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