The hinge region

A separately encoded 'hinge' region is inserted between the CH1 and CH2 domains. Portions of the hinge regions of two human lgGl antibodies can be seen in Figures 3 and 4. In the human and murine IgGl subclasses, the initial part of the hinge region supplies the half-cysteine residue which forms the interchain disulfide bond with the L chain (see Figure 4). Its half-cystine counterpart in the L chain occupies the C-terminal location in a k chain and the penultimate position in a k chain. Disulfide bonds linking the two heavy chains are found in a relatively rigid 'core' segment (Cys-Pro-Pro-Cvs-Pro) of the hinge region. Segments flanking this core section are responsible for the flexibility suggested by the name 'hinge'. Papain hydrolyzes peptide bonds among residues 6-10 of the upper flexible segment ('proximal hinge') between the H-H and the H-L interchain disulfide bonds to produce Fabs. Pepsin cleaves the lower flexible segment ('distal hinge') after the disulfide bonds ro release a (Fab')2 fragment.

In the most prevalent subclass (IgGl) of human

Anligcn tundirĂ­a site

Figure 5 Model of the Meg lgG1 myeloma protein, in which a discrete hinge region is deleted. The connecting segments between CH1 and Ch2 are derived exclusively from the first seven residues of the CH2 gene product. Note that these connecting segments cross in the model. Because they cannot form a disulfide bond with the heavy chain, the appropriate half-cysteine residues in the two light chains form a disulfide bond across the crystallographic dyad relating the two halves of the lgG1 molecule. The shortening of the heavy chain, together with the inter-light chain disulfide bond, lead to different structural relationships between the light and heavy chains, including a very large, concave active site at the tips of the Fab arms. Note the large structural differences between the constrained Fc region in this intact lgG1 molecule and the Fc fragment released from a conventional lgG1 molecule by the action of papain (as seen in Figure 3).

IgG molecules, the hinge region typically consists of only 15 residues, while the corresponding segment in IgM and IgE molecules is sufficiently large to be considered an entire C domain. When hinge regions are present, as in the two human proteins Kol IgGl and Zie IgG2, the Fab portions of these molecules adopt ordered structures in the crystals, while the Fc regions are 'disordered' and therefore cannot be analyzed by X-ray diffraction techniques. This causes the crystallographic structure of the intact Kol IgGl immunoglobulin (Figure 4) to resemble a (Fab')2 fragment.

In a small minority (1-2%) of IgG proteins, the hinge region is deleted from the heavy chain. These proteins (e.g. Dob, Lec and McG IgGl immunoglobulins) are less flexible than molecules with hinge regions. However, the loss of flexibility appears to be advantageous for uniform packing in crystal lattices. Such proteins have therefore proved to be favorable for X-ray crystallographic analyses. The crystal structure of the McG IgGl immunoglobulin is shown in Figure 5.

When the hinge region is deleted, the interchain half-cystine residue on the light chain can no longer pair with a heavy chain partner. Usually, alternative pairing is established by formation of an interchain disulfide bond with the second light chain in the antibody molecule (see Figure 5, center S-S bond). Although the effects are difficult to assess quantitatively, the formation of this disulfide bond partially restricts the freedom of the Fab arms to move independently and thus accentuates the loss of flexibility associated with a hinge deletion alone. Since the Fc region is pulled tightly up into the junction of the Fab arms, its rotational or translational mobility is also severely impaired.

Again we have an example of how the delineations of unusual features can lead to a better understanding of the highly evolved and efficient structures of the dominant molecules in 'normal' sera. Just as the pathological effects of incomplete glycosylation focus attention on the role of carbohydrates in keeping IgG antibodies soluble, the deletion of the hinge and the formation of an L-L disulfide bond help us understand the tremendous advantages of a flexible hinge in the tracking and cross-linking of deleterious antigens.

See also: Antigen-binding site; Domains, immuno-globulin-type; IgA; IgD; IgE; IgG; IgM; Joining J chain; Antibody-antigen complexes, three-dimensional structures.

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