The Recognition and Role of Variable Regions

The existence of such variation in the N-terminal half of the light chains while the C-terminal half remained constant was a new phenomenon in protein chemistry. As the number of sequences increased and as such data on mouse Bence Jones proteins and later on heavy chains of immunoglobulins were accumulated, it became clear that understanding the nature of the structural and genetic basis for the variable domains of both chains was crucial to understanding antibody specificity. 

Saul et al. (1978) and Poljak et al. (1974) note the superimposability of the a-carbons of Phe-Gly-Gly-Gly residues 98-101 in VL and Trp-Gly-Gln-Gly in residues 103-106 in VH of Newm. They consider this as evidence against these glycines functioning as a pivot and attribute the invariance of the Gly residues to the need for VH-VL and intrasubunit contacts and the limited space available in this portion of the molecule. Whether these invariant Gly residues can serve as a pivot will ultimately be established by comparisons of the filled and empty sites when a ligand specific for the entire site is available. 

To distinguish further between framework residues, which could show the usual mutational noise, and those positions which might be involved in antibody complementarity and thus show much greater variation, a parameter termed variability was defined by Wu and Kabat (1970)  

The variability equation was used to examine the sequences of the heavy chains as soon as a sufficient number became available (Kabat 

High variability was noted also at positions 81, 83, 84, 85 when human heavy chains were examined, and this is considered another hypervariable region by Capra and Kehoe (1974). Unlike the other hypervariable regions it became less marked when several species of heavy chain were considered. It is not seen in mouse heavy chains (Vrana et al., 1977) and is not apparent when all heavy-chain data are combined (Fig. 6). Residues 84 and 85 of rabbit heavy chains, however, are involved in a allotypic specificity (Ansari et al., 1976 Mage, 

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