Complementary Interactions between Proteins and Ligands: The Immune System and Immunoglobulins: -Antibodies Have Two Identical Antigen-Binding Sites

Immunoglobulin G (IgG) is the major class of anti-body molecule and one of the most abundant proteins in the blood serum. IgG has four polypeptide chains: two large ones, called heavy chains, and two light chains, linked by noncovalent and disulfide bonds into a complex of Mr 150,000. The heavy chains of an IgG molecule interact at one end, then branch to interact separately with the light chains, forming a Y-shaped molecule (Fig. 5–23). At the “hinges” separating the base of an IgG molecule from its branches, the immunoglobulin can be cleaved with proteases. Cleavage with the protease papain liberates the basal fragment, called Fc because it usually crystallizes readily, and the two branches, called Fab, the antigen-binding fragments. Each branch has a single antigen-binding site.

The fundamental structure of immunoglobulins was first established by Gerald Edelman and Rodney Porter. Each chain is made up of identifiable domains; some are constant in sequence and structure from one IgG to the next, others are variable. The constant domains have a characteristic structure known as the immunoglobulin fold, a well-conserved structural motif in the all β class of proteins. There are three of these constant domains in each heavy chain and one in each light chain. The heavy and light chains also have one variable domain each, in which most of the variability in amino acid residue sequence is found. The variable domains associate to create the antigen-binding site (Fig. 5–24).

In many vertebrates, IgG is but one of five classes of immunoglobulins. Each class has a characteristic type of heavy chain, denoted α, δ, Σ, γ, and μ for IgA, IgD, IgE, IgG, and IgM, respectively. Two types of light chain, k and λ, occur in all classes of immunoglobulins. The overall structures of IgD and IgE are similar to that of IgG. IgM occurs either in a monomeric, membrane bound form or in a secreted form that is a cross-linked pentamer of this basic structure (Fig. 5–25). IgA, found principally in secretions such as saliva, tears, and milk, can be a monomer, dimer, or trimer. IgM is the first antibody to be made by B lymphocytes and is the major antibody in the early stages of a primary immune response. Some B cells soon begin to produce IgD (with the same antigen-binding site as the IgM produced by the same cell), but the unique function of IgD is less clear. The IgG described above is the major antibody in secondary immune responses, which are initiated by memory B cells. As part of the organism’s ongoing immunity to antigens already encountered and dealt with, IgG is the most abundant immunoglobulin in the blood. When IgG binds to an invading bacterium or virus, it activates certain leukocytes such as macrophages to engulf and destroy the invader, and also activates some other parts of the immune response. Yet another class of receptors on the cell surface of macrophages recognizes and binds the Fc region of IgG. When these Fc receptors bind an antibody-pathogen complex, the macrophage engulfs the complex by phagocytosis (Fig. 5–26).

FIGURE 5–23 The structure of immunoglobulin G. (a) Pairs of heavy and light chains combine to form a Y-shaped molecule. Two antigen binding sites are formed by the combination of variable domains from one light (VL) and one heavy (VH) chain. Cleavage with papain separates the Fab and Fc portions of the protein in the hinge region. The Fc portion of the molecule also contains bound carbohydrate.

(b) A ribbon model of the first complete IgG molecule to be crystallized and structurally analyzed (PDB ID 1IGT). Although the molecule contains two identical heavy chains (two shades of blue) and two identical light chains (two shades of red), it crystallized in the asymmetric conformation shown. Conformational flexibility may be important to the function of immunoglobulins.

FIGURE 5–24 Binding of IgG to an antigen. To generate an optimal fit for the antigen, the binding sites of IgG often undergo slight conformational changes. Such induced fit is common to many protein-ligand interactions.

FIGURE 5–25 IgM pentamer of immunoglobulin units. The pentamer is cross-linked with disulfide bonds (yellow). The J chain is a polypep tide of Mr 20,000 found in both IgA and IgM.

FIGURE 5–26 Phagocytosis of an antibody-bound virus by a macrophage. The Fc regions of the antibodies bind to Fc receptors on the surface of the macrophage, triggering the macrophage to engulf and destroy the virus.

IgE plays an important role in the allergic response, interacting with basophils (phagocytic leukocytes) in the blood and histamine-secreting cells called mast cells that are widely distributed in tissues. This immunoglobulin binds, through its Fc region, to special Fc receptors on the basophils or mast cells. In this form, IgE serves as a kind of receptor for antigen. If antigen is bound, the cells are induced to secrete histamine and other biologically active amines that cause dilation and increased permeability of blood vessels. These effects on the blood vessels are thought to facilitate the move ment of immune system cells and proteins to sites of inflammation. They also produce the symptoms normally associated with allergies. Pollen or other allergens are recognized as foreign, triggering an immune response normally reserved for pathogens.

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المزيد

مواضيع ذات صلة

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