Ig Constant Region Effects on Variable Region Structure and Function

Abstract

The adaptive humoral immune response is responsible for the generation of antimicrobial proteins known as immunoglobulin molecules or antibodies. Immunoglobulins provide a defense system against pathogenic microbes and toxins by targeting them for removal and/or destruction. Historically, antibodies have been thought to be composed of distinct structural domains known as the variable and constant regions that are responsible for antigen binding and mediating effector functions such as opsonization and complement activation, respectively. These domains were thought to be structurally and functionally independent. Recent work has revealed however, that in some families of antibodies, the two regions can influence each other. We will discuss the body of work that led to these observations, as well as the mechanisms that have been proposed to explain how these two different antibody regions may interact in the function of antigen binding.

Keywords: constant region; function; immunoglobulin; isotype; structure; variable region.

Figure 1

Crystal structure of intact IgG₁ (PDB ID: 1IGY). Adapted from Harris et al. (1998).

Figure 2

Relationships between permissive and non-permissive V region sequences. Immunoglobulins with differing C regions and identical V regions were identified in the literature (Table 2). VH and VL amino acid sequences were found for 24 of these unique antibodies (11 human and 13 murine, Table 2). Human sequences were grouped by (A) VH and (B) VL sequences. Murine sequences were also grouped by (C) VH and (D) VL sequences. For each group, a dendrogram was constructed through hierarchical average-linkage clustering with pairwise sequence similarity calculated as the Levenshtein distance. Leaf labels in the dendrograms are colored according to whether changes in the constant region for that antibody were permissive (green) or non-permissive (red) of specificity changes. The top V-region gene candidate for each amino acid sequence was determined with the IGBLAST blastp program using default parameters for either the human or mouse database (IGBLAST). Leaf labels in the dendrograms are of the form “seqID_top V-region gene hit,” where seqID matches the sequence ID given in Table 2.