The adaptive immune system of jawed vertebrates pre-emptively enables specific responses to pathogens and cultivates memory of past encounters.  Key components of this system are the B- and T- lymphocytes and their “rearranging” heterodimeric receptors; the B-cell receptor (the soluble form being the canonical “antibody”) and the T-cell receptor.  Both are built from the same building block, the immunoglobulin (Ig) domain fold.  The phylogenetic pathway for the emergence of these receptors is unclear as they are absent in the genomes of modern jawless vertebrates (hagfish and lampreys), but are present in their jawed cousins, the sharks and rays. Hence, their emergence is believed to have occurred when these chordate lineages diverged, some 500 million years ago.

The modern heterodimeric Ig receptors are proposed to have evolved from primordial homodimeric receptors through processes of gene duplication and diversification. We have used laboratory evolution to reconstruct a homodimeric proto-receptor type molecule and investigate how such a symmetric receptor is capable of interacting with protein antigens.  Crystal structures of two such Ig receptor-antigen complexes reveal that both of the Ig halves contribute to an extensive interface capable of high affinity interactions with asymmetric targets.  Symmetry mismatch is accommodated either by the utilization of different side chain rotamers within otherwise identical complementarity determining regions (CDRs) (conformational plasticity), or by context-dependent differential use of CDRs (selective recruitment).  These data provide structural evidence for the evolutionary origins of modern Ig-based  antibodies and receptors and support the thesis that these molecules arose from simple Ig-domain precursors.