A typical L chain will thus mass approximately 25 kDa, and a three C domain Cγ H chain with its hinge will mass approximately 55 kDa. H chains with three C domains tend to include a spacer hinge region between the first (C H1) and second (C H2) domains. Both Ig L chains contain only one C domain, whereas Ig H chains contain either three or four such domains. ( 1) Each V or C domain consists of approximately 110–130 amino acids, averaging 12,000–13,000 kDa. Each component chain contains one NH2-terminal “variable (V) IgSF domain and one or more COOH-terminal “constant” (C) IgSF domains, each of which consists of two sandwiched β pleated sheets ‘pinned’ together by a disulfide bridge between two conserved cysteine residues. ( 1– 3) They consist of two heavy (H) and two light (L) chains ( Figure 1), where the L chain can consist of either a κ or a λ chain. Immunoglobulins (Igs) belong to the eponymous immunoglobulin super-family (IgSF). The immunoglobulin domain: the basic IgSF building block The molecular mechanisms that permit these many and varied functions are the focus of this chapter. Immunoglobulins also serve two purposes: that of cell-surface receptors for antigen which permit cell signaling and cell activation and that of soluble effector molecules which can individually bind and neutralize antigens at a distance. This property of adjustable binding depends on a complex array of mechanisms that alter the DNA of individual B cells. However, while individual immunoglobulin also bind a limited and defined set of ligands, immunoglobulins as a population can bind to a virtually unlimited array of antigens sharing little or no similarity. Typically, receptors bind to a limited and defined set of ligands. More than 100 years of investigation into the structure and function of immunoglobulin has only served to emphasize the complex nature of this protein. “Sizing” columns were then used to separate immunoglobulins into those that were “heavy” (IgM), “regular” (IgA, IgE, IgD, IgG), and “light” (light chain dimers). Absorption of the serum against the antigen depleted the gamma-globulin fraction, yielding the terms gamma globulin, immunoglobulin (Ig), and IgG. In 1939, Tiselius and Kabat used electrophoresis to separate immunized serum into albumin, alpha-goblulin, beta-globulin, and gamma-globulin fractions. Thus, an antibody and its antigen represent a classic tautology. The term antigen is a contraction of this term. Subsequently, the substance which induces the production of an antibody was referred to as the ‘Antisomatogen+Immunkörperbildner’, or that agent which induces the antibody. The following year, reference was made to ‘Antikörper’, or antibodies, in studies describing the ability of the agent to discriminate between two immune substances. ![]() In 1890, von Behring and Kitasato reported the existence of an agent in the blood that could neutralize diphtheria toxin. The constant domains of the H chain can be switched to allow altered effector function while maintaining antigen specificity. IgG can be split into four subclasses, IgG1, IgG2, IgG3, and IgG4, each with its own biologic properties and IgA can similarly be split into IgA1 and IgA2. Each class defines the IgM, IgG, IgA, IgD, and IgE isotypes. There are five main classes of heavy chain C domains. The three CDRs of the H chain are paired with the three CDRs of the L chain to form the antigen binding site, as classically defined. ![]() Each V domain can be split into three regions of sequence variability, termed the complementarity determining regions, or CDRs, and four regions of relatively constant sequence termed the framework regions, or FRs. ![]() The variable domains are created by means of a complex series of gene rearrangement events, and can then be subjected to somatic hypermutation after exposure to antigen to allow affinity maturation. They can be separated functionally into variable (V) domains that binds antigens and constant (C) domains that specify effector functions such as activation of complement or binding to Fc receptors. Immunoglobulins are heterodimeric proteins composed of two heavy (H) and two light (L) chains.
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