Biochemistry, Vol. 3 - A. Lehninger 1985

Molecular Mechanisms of Genetic Information Transfer
More on Genes: Repair, Mutation, Recombination, and Cloning
Antibody Diversity Results from Translocation and Recombination

One of the most unusual types of genetic recombination occurs during The formation of genes that determine the synthesis of various Antibodies in vertebrates. Antibodies, or IMMUNOGLOBULINS, are Proteins produced by vertebrate lymphocytes (immunocytes) in response to the invasion of a foreign macromolecule, known as an antigen (Section 6.11). Each type of antigen is capable of binding to a specific type of immunocyte, stimulating the growth and division of these Cells and leading to the formation of a unique clone—a line of completely identical immunocytes. The cells of such a clone produce only a single kind of immunoglobulin, which specifically binds exclusively to the antigen that induced their proliferation. As a result of the antigen-antibody interaction, a complex is formed in which the antigen typically loses its biological activity. What is truly remarkable is that The Human Body can synthesize literally millions of Different types of antibodies, each capable of binding to just one of the millions of potential Antigens the Organism might encounter. Antibodies are produced not only against the vast majority of proteins from other animals, Bacteria, Viruses, parasites, and plants, but against virtually any macromolecule, even those of artificial origin.

One might get the impression that in order to synthesize such a vast array of antibodies—each interacting with only one of many millions of possible antigens—the organism must contain a corresponding number of distinct genes for every single antibody. For a long time, this seemed implausible. Human Cell nuclei simply do not contain enough DNA to encode millions of different antibodies In addition to the many thousands of conventional proteins responsible for the Structure, METABOLISM, and individuality of the human body.

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Fig. 30-16. Structure of an antibody molecule. The molecule consists of two light (L) chains and two heavy (H) chains, each containing a variable (V) region (red) and a constant (C) region (gray). The constant Regions of the heavy chains are composed of three distinct domains: C_н1, C_н2, and C_н3. The molecule contains A large number of Disulfide Bonds and carbohydrate residues attached to the heavy chains.

The answer to this mystery came from studies of the Structure of antibodies and the genes that encode them. Figure 30-16 illustrates The structure of an antibody with a molecular mass of approximately 160,000. An antibody molecule is composed of two heavy, or long, polypeptide chains (446 amino acid residues each) and two light, or short, chains (214 amino acid residues each). The chains are linked together by transverse disulfide bonds; in addition, both chains contain internal -S—S- bonds. Each heavy and light chain contains a region with an invariant Amino Acid Sequence characteristic of a given species, known as the constant, or C-region. Each chain also contains a variable V-region, The amino acid sequence of which presumably differs among various types of antibodies. The constant region of the heavy chains consists of three domains with similar Amino acid sequences. The antibody molecule contains two antigen-binding sites, each located in a cleft (or "pocket") between the ends of the variable regions of the heavy and light chains. A molecular model of an antibody is shown in Figure 30-17.

The presence of constant and variable regions in antibodies long ago led scientists to suggest that the DNA directing the synthesis of light chains is formed by the splicing of two genes—one encoding the variable region and the other the constant region. Evidence supporting this hypothesis was obtained by Susumu Tonegawa and his coworkers, who demonstrated that the genes encoding the constant and variable parts of light chains of a specific type are located very close together in the DNA of immunocytes producing that type of molecule, whereas in the DNA of another immunocyte Lineage incapable of producing this type of light chain, they are situated far apart. Tonegawa et al. concluded that immunocytes can select DNA segments encoding the variable parts of an antibody molecule from different, widely separated regions of The Cell genome and relocate them to a position immediately downstream of the Gene encoding the constant part of that particular light chain type. Once the genes are joined into a single unit, RNA polymerase can direct the synthesis of a single mRNA molecule encoding the entire light chain.

Subsequent research revealed that the DNA encoding the variable regions of both light and heavy chains is composed of several types of genes that can change their positions and assemble in diverse combinations (Figure 30-18). The DNA determining the variable regions of antibodies is assembled from approximately four hundred different variable (V) genes, about twelve so-called diversity (D) genes, and four joining (J) genes. The combinatorial assortment of these genes makes it possible to generate DNA for more than 20,000 (or even a greater number of) variable regions. These genes, in turn, undergo additional modifications in their nucleotide sequences and join with various DNA segments encoding constant regions, ultimately producing millions of different genes responsible for antibody synthesis. While many questions regarding antibody synthesis still await Answers, it is already clear that the rearrangement and recombination of genes, or gene segments, is a highly efficient and precisely regulated process by which immunocytes can generate antibodies against virtually any macromolecule.

Fig. 30-17. Model of immunoglobulin structure based on X-Ray Diffraction data.