All antibodies exhibit a similar basic architecture, with two light chains and two heavy chains. Each light chain contains an N-terminal variable and a C-terminal constant region, whereas the heavy chain contains one N-terminal variable and three or four C-terminal regions. In simple terms, the conformation of most antibodies can be thought of as a capital letter Y, in which each of the two arms of the Y corresponds to an antigen-binding fragment (Fab) and the base of the Y corresponds to the Fc region (called the crystallizable fragment, based on the propensity of IgG-Fc to form crystals). Each Fab is composed of a light chain and the two N-terminal Ig domains of a heavy chain and is connected by a hinge region to the Fc, which is a dimer of the two C-terminal domains of each heavy chain. Regions of highly variable sequence within the light and heavy chains in each Fab combine to form a specific antigen-binding site, whereas the Fc region is comprised of constant regions of the heavy chains and interacts with isotype-specific Fc receptors. Fc receptors are responsible for a number of important biological processes including activation of immune effector functions, transport of antibodies to specific cellular locations, and protection of secretory antibodies from proteolytic degradation. The five human classes of antibody (IgG, IgE, IgD, IgM, and IgA) are defined by the features of their heavy chains, which differ in their sequences, the number and position of their disulfide bonds, the number and type of carbohydrates attached, the length of their hinge regions, and the number of C-terminal domains (Janeway et al. 1999). High-resolution structures of intact IgG (Harris et al. 1992,1998) and fragments of IgG (Huber et al. 1976; Matsushima et al. 1978), IgA (Satow et al. 1986; Suh et al. 1986; Herr et al. 2003), IgM (Corper et al. 1997), and IgE (Wurzburg et al. 2000; Wan et al. 2002) have been solved by X-ray crystallography, as well as low-resolution structures of intact IgA1 (Boehm et al. 1999), IgA2 (Furtado et al. 2004), and IgM (Perkins et al. 1991) by small-angle X-ray and neutron scattering.
IgG, the most abundant serum Ig, was the first antibody isotype for which high-resolution structural information became available. Crystal structures of IgG Fab fragments and Fab-antigen complexes revealed a four-domain P-barrel arrangement and showed that, in some cases, the antibody combining site is a concave pocket into which the antigen binds. In other cases, portions of the antibody protrude into the antigen (reviewed in Wilson et al. 1991). IgG-Fc fragments (called Fcy) also have four P-barrel Ig domains with extensive contact surface between the Cy3 domains and no protein-protein contacts between the Cy2 domains (Huber et al. 1976). An N-linked carbohydrate attached to the inner surface of the Cy2 domain interacts with the domain through both polar and hydrophobic residues (Deisenhofer 1981). The N-glycans attached to each heavy chain occupy the space between the Cy2 domains and mediate the proper domain orientation required for binding to Fcy receptors (Fig. 2a). Intact IgG structures have provided several snapshots of these flexible molecules with an overall Y or T shape but each with an asymmetric arrangement of the Fab and Fc fragments, consistent with the flexible nature of antibodies (Harris et al. 199, 1998). Another antibody isotype, IgE, is present at low concentrations in serum and primarily targets parasites. The interaction of IgE with its receptor is responsible for inflammation and allergic reactions. The crystal structure of IgE-Fc (Fce) revealed that the overall structure is very similar to Fcy, including the position of the N-linked carbohydrate between the Ce3 domains, which is an analogous location to the carbohydrate on Cy2 in IgG (Garman et al. 2000; Wurzburg et al. 2000). However, IgE (and IgM) contain an Ig domain in place of the flexible hinge region, and the crystal structure of Fce containing this hingelike Ig domain revealed that it is folded back onto the surface of the Fc region, presumably introducing a pronounced bend in the intact IgE structure (Wan et al. 2002).
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