Molecular Biology: Protein Structure and Functions - Stepanov V.M. 2005

Immunoglobulins
The Diversity of Immunoglobulins

The Organization of immunoglobulin structural genes is quite unique, designed to enable the generation of a vast diversity of Antibodies. The genes encoding light and heavy chains are assembled from smaller Gene segments. Some of these—most notably the exceptionally numerous ones—encode the variable domains V_L and V_H (V genes), while others, which are far fewer in number, encode the constant Regions of the molecule (C genes).

For instance, the constant domains of light chains are encoded by several genes, leading to the synthesis of two light chain types: ӕ and λ. The human haploid genome contains a single ӕ-chain gene and multiple λ-chain genes. The number of genes encoding variable domains is significantly greater. Specifically, there are around 100 Vӕ genes that specify the Amino acid sequences of ӕ-type light chain variable domains.

It is worth noting that a small segment of the L-chain located immediately upstream of the constant region—designated as J (from 'joining')—is encoded separately and is likewise variable. During B-lymphocyte maturation, L-chain genes are assembled from these segments through a recombination process that unites V_L-J_L-C_L genes, ultimately yielding a remarkable variety of light ӕ-chains.

Similarly, heavy chain genes are formed from V_H genes (numbering around 100) via recombination with D_H, J_H, and C_H genes, resulting in the configuration V_H—D_H—J_H—C_H. The total number of possible binding site variants thus reaches approximately 10 million. This figure increases even further when accounting for somatic Mutations, which introduce additional Amino Acid Substitutions within the immunoglobulin variable domains.

This distinctive mechanism of immunoglobulin gene formation ensures the generation of an immense diversity of amino acid sequences. Moreover, the domain organization of these Proteins, combined with the concentration of substitutions within a few hypervariable regions, enables the creation of antibody binding sites with extraordinarily diverse surface topography and functional group distributions. Consequently, a surface complementary to virtually any given antigen can always be found.

In addition to the aforementioned IMMUNOGLOBULINS G, there are four other classes of immunoglobulins: M, A, E, and D. Their molecules are also domain-based and follow the same structural principle. In immunoglobulins M and E, the heavy chains include an extra domain—C_μ4 and C_ε4, respectively. In immunoglobulins A and M, the C-terminal regions of the heavy chains are linked together with the aid of a special J chain. There are other structural differences as well, notably in the content and distribution of carbohydrate chains. Immunoglobulin M forms pentamers (L₂H₂)₅. Membrane-bound immunoglobulins belonging to classes M and D feature small domains at the C-termini of their heavy chains, composed predominantly of hydrophobic Amino Acids that act as an anchor, securing the immunoglobulin molecule to the outer Cell membrane surface.

Thus, the domain-based principle of immunoglobulin Structure and function is exceptionally versatile, utilizing a single structural motif to generate a rich repertoire of antigen-binding proteins. It is likely that certain cell Membrane Receptors are constructed following a similar blueprint.