Structural correlates of immunoglobulin diversity.

VL and VH domains, from different species and with widely different primary structures, interact with each other in the same way to create the globular FV region. Much of the FV is a highly conserved framework structure that is probably common to most, if not all, mammalian FV regions. The extensive contoured frontal surface of the FV is composed of highly variable polypeptide segments (Wu-Kabat complementarity-determining regions). These segments are derived from parts of VL, VH, JH gene products and most of the D gene product. This surface is currently considered to be the most likely location of the antigen-binding sites. The firm immunochemical data based on identification of contacting amino acids supporting this location are still, however, very fragmentary. VL and VH gene products form a large part of the potential antigen-reactive surface. Hence, combinations of different VL and VH gene products are the largest source of structural diversity. The JL and JH gene products have chiefly structural functions in maintaining domain architecture and controlling some interactions between VL and VH domains. The VL-J junction amino acid can provide unique structural properties in the deeper accesses of the potential antigen reaction surface. The VHD-JH junction is more superficial and could be, but has not yet been, directly implicated in antigen binding. The D gene product and the additional amino acids associated with the (VH-D-JH) rearrangement process do determine a substructural part of the potential antigen reactive surface. The D gene product (a connecting segment between two beta strands) can have many different secondary structures. Functionally, the D region product could interact with VL-CDR-1 amino acids to create a specific contour of the antigen reaction surface. Curiously, primary structural variations in H3 have not yet been directly implicated in antigen binding. Much remains to be learned about the role of VH-D-JH rearrangement in antibody diversity. The major genetic factors in creating structural diversity are the multiple VL and VH gene libraries. The gene rearrangement process provides a further amplification. Somatic mutations are yet another additional mechanism.