Most of the sequence differences and variability among different antibodies are confined to three short stretches in the V region of the heavy chain and to three stretches in the V region of the light chain. These segments of the greatest diversity are known as hypervariable regions. They correspond to three protruding loops connecting adjacent strands of the β sheets that make up the V domains of Ig heavy- and light chain proteins (Fig. 1). The hypervariable regions are each about 10 amino acid residues long, and they are held in place by the more conserved framework sequences that make up the Ig domain of the V region. Because these sequences form a surface that is complementary to the three-dimensional shape 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. Sequence differences among the CDRs of different antibody molecules contribute to dis tinct interaction surfaces and therefore to specificities of individual antibodies. The CDR3s of both the VH segment and the VL segment are the most variable of the CDRs. As we will dis cuss in Chapter 8, there are special mechanisms for generating more sequence diversity in CDR3 than in CDR1 and CDR2. 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 create an antigen-binding surface. The hypervariable loops can be thought to resemble fingers protruding from each variable domain, with three fingers from the heavy chain and three fingers from the light chain coming together to form the antigen-binding site (Fig.2). 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. Confinement of the sequence variability to three short stretches allows the basic structure of all antibodies to be maintained, despite the variability that contributes to the specificities of different antibodies.

Fig1. Hypervariable regions in immunoglobulin (Ig) molecules. (A) The vertical lines 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 analysis indicates that the most variable residues are clustered in three “hypervariable” regions, colored in blue, yellow, and red, corresponding to complementarity-determining region 1 (CDR1), CDR2, and CDR3, respectively. Three hypervariable regions are also present in heavy chains (not shown). This way of displaying amino acid variability in Ig molecules is called a Kabat-Wu plot after the two scientists who devised the assay. (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). Note that in Fig. 5.2 an Ig constant domain, which does not have CDRs, is depicted. (A, Courtesy the late Dr. EA Kabat, Department of Microbiology, Columbia University College of Physicians and Surgeons, New York.)

Fig2. Binding of an antigen by an antibody. (A) A schematic view of complementarity-determining regions (CDRs) generating an antigen-binding site. CDRs from the heavy chain and the light chain are loops that protrude from the surface of the two immunoglobulin V domains and in combination create an antigen binding surface. (B) This model of a globular protein antigen (hen egg lysozyme) bound to an antibody molecule shows how the antigen-binding site can accommodate soluble macromolecules in their native (folded) conformation. The heavy chains of the antibody are red, the light chains are yellow, and the antigen is blue. (C) A view of the interacting surfaces of a hen egg lysozyme (in green) and a Fab fragment of a monoclonal anti hen egg lysozyme antibody (VH in blue and VL in yellow) is provided. The residues of the hen egg lysozyme and of the Fab fragment that interact with each other are shown in red. A critical glutamine residue on lysozyme (in magenta) fits into a “cleft” in the antibody. (B, Courtesy Dr. Dan Vaughn, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. C, From Amit AG, Mariuzza RA, Phillips SE, Poljak RJ. Three dimensional structure of an antigen antibody complex at 2.8 A resolution. Science. 1986;233:747–753.)

Crystallographic analyses of antigen-antibody complexes show that the amino acid residues of the CDRs form multiple contacts with bound antigens (see Fig. 2). The most extensive contact is with the third hypervariable region (CDR3). However, antigen binding is not solely a function of the CDRs, and framework residues may also contact the antigen.

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مواضيع ذات صلة

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Structural Features of Antibody Constant Regions

General Features of Antibody Structure

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Mechanisms that Limit Innate Immune Responses

Stimulation of Adaptive Immunity

Systemic and Pathologic Consequences of Inflammation

Immuno microscopy

V(D)J Recombination

Role of Macrophages in Tissue Repair

Ingestion and Killing of Microbes by Activated Phagocytes

Sequence of Events in Inflammation: Vascular Changes and Leukocyte Migration Into Tissues