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FIGURE 5-5 Hypervariable regions in Ig molecules. A, Kabat-Wu plot of amino acid variability in Ig molecules. The histograms depict the extent of variability, defined as the number of differences in each amino acid residue among various independently sequenced Ig light chains, plotted against amino acid residue number, measured from the amino terminus. This method of analysis, developed by Elvin Kabat and Tai Te Wu, indicates that the most variable residues are clustered in three "hypervariable" regions, colored in blue, yellow, and red, corresponding to CDR1, CDR2, and CDR3, respectively. Three hypervariable regions are also present in heavy chains. (Courtesy of Dr. E. A. Kabat, Department of Microbiology, Columbia University College of Physicians and Surgeons, New York.) B, Three-dimensional view of the hypervariable CDR loops in a light chain V domain. The V region of a light chain is shown with CDR1, CDR2, and CDR3 loops, colored in blue, yellow, and red, respectively. These loops correspond to the hypervariable regions in the variability plot in A. Heavy chain hypervariable regions (not shown) are also located in three loops, and all six loops are juxtaposed in the antibody molecule to form the antigen-binding surface (see Fig. 5-6).

FIGURE 5-5 Hypervariable regions in Ig molecules. A, Kabat-Wu plot of amino acid variability in Ig molecules. The histograms depict the extent of variability, defined as the number of differences in each amino acid residue among various independently sequenced Ig light chains, plotted against amino acid residue number, measured from the amino terminus. This method of analysis, developed by Elvin Kabat and Tai Te Wu, indicates that the most variable residues are clustered in three "hypervariable" regions, colored in blue, yellow, and red, corresponding to CDR1, CDR2, and CDR3, respectively. Three hypervariable regions are also present in heavy chains. (Courtesy of Dr. E. A. Kabat, Department of Microbiology, Columbia University College of Physicians and Surgeons, New York.) B, Three-dimensional view of the hypervariable CDR loops in a light chain V domain. The V region of a light chain is shown with CDR1, CDR2, and CDR3 loops, colored in blue, yellow, and red, respectively. These loops correspond to the hypervariable regions in the variability plot in A. Heavy chain hypervariable regions (not shown) are also located in three loops, and all six loops are juxtaposed in the antibody molecule to form the antigen-binding surface (see Fig. 5-6).

variability are discussed in Chapter 8. In an antibody molecule, the three hypervariable regions of a VL domain and the three hypervariable regions of a VH domain are brought together to form an antigen-binding surface. The hypervariable loops can be thought to be like fingers protruding from each variable domain, three fingers from the heavy chain and three fingers from the light chain coming together to form an antigen-binding site (Fig. 5-6). Because these sequences form a surface that is complementary to the three-dimensional structure of the bound antigen, the hypervariable regions are also called complementarity-determining regions (CDRs). Proceeding from either the VL or the VH amino terminus, these regions are called CDR1, CDR2, and CDR3. The CDR3s of both the VH segment and the VL segment are the most variable of the CDRs. As we will discuss in Chapter 8, there are special mechanisms for generating more sequence diversity in CDR3 than in CDR1 and CDR2. Sequence differences among the CDRs of different antibody molecules contribute to distinct interaction surfaces and therefore to specificities of individual antibodies. The ability of a V region to fold into an Ig domain is mostly determined by the conserved sequences of the framework regions adjacent to the CDRs. Confining the sequence variability to three short stretches allows the basic structure of all antibodies to be maintained despite the variability among different antibodies.

Antigen binding by antibody molecules is primarily a function of the hypervariable regions of VH and VL. Crys-tallographic analyses of antigen-antibody complexes show that the amino acid residues of the hypervariable regions form multiple contacts with bound antigen (see Fig. 5-6). The most extensive contact is with the third hypervariable region (CDR3), which is also the most variable of the three CDRs. However, antigen binding is not solely a function of the CDRs, and framework residues may also contact the antigen. Moreover, in the binding of some antigens, one or more of the CDRs may be outside the region of contact with antigen, thus not participating in antigen binding.

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