STRUCTURAL-ANALYSIS OF THE NURSE SHARK (NEW) ANTIGEN RECEPTOR (NAR) -MOLECULAR CONVERGENCE OF NAR AND UNUSUAL MAMMALIAN IMMNNOGLOBULINS

We recently have identified an antigen receptor in sharks called NAR ( new or purse shark antigen receptor) that is secreted by splenocytes b ut does not associate with Ig light (L) chains. The NAR variable (V) r egion undergoes high levels of somatic mutation and is equally diverge nt from both Ig and T cell receptors (TCR). Here we show by electron m icroscopy that NAR V regions, unlike those of conventional Ig and TCR, do not form dimers but rather are independent, flexible domains. This unusual feature is analogous to bona fide camelid IgG in which modifi cations of Ig heavy chain V (V-H) sequences prevent dimer formation wi th L chains. NAR also displays a uniquely flexible constant (C) region . Sequence analysis and modeling show that there are only two types of expressed NAR genes, each having different combinations of noncanonic al cysteine (Cys) residues in the V domains that likely form disulfide bonds to stabilize the single antigen-recognition unit. In one NAR cl ass, rearrangement events result in mature genes encoding an even numb er of Cys (two or four) in complementarity-determining region 3 (CDR3) , which is analogous to Cys codon expression in an unusual human diver sity (D) segment family. The NAR CDR3 Cys generally are encoded by pre ferred reading frames of rearranging D segments, providing a clear des ign for use of preferred reading frame in antigen receptor D regions. These unusual characteristics shared by NAR and unconventional mammali an Ig are most likely the result of convergent evolution at the molecu lar level.