Immunoglobulins Possess Multiple Domains Based on the Immunoglobulin Fold

Careful analysis of the amino acid sequences of immunoglob-ulin heavy and light chains showed that both chains contain several homologous units of about 110 amino acid residues. Within each unit, termed a domain, an intrachain disulfide bond forms a loop of about 60 amino acids. Light chains contain one variable domain (VL), and one constant domain (CL); heavy chains contain one variable domain (VH), and either three or four constant domains (CH1, CH2, CH3, and Ch4), depending on the antibody class (Figure 4-6).

X-ray crystallographic analysis revealed that im-munoglobulin domains are folded into a characteristic compact structure called the immunoglobulin fold. This structure consists of a "sandwich" of two p pleated sheets, each containing antiparallel p strands of amino acids, which are connected by loops of various lengths (Figure 4-7). The p strands within a sheet are stabilized by hydrogen bonds that connect the -NH groups in one strand with carbonyl groups of an adjacent strand (see Figure 4-4). The p strands are characterized by alternating hydrophobic and hydrophilic amino acids whose side chains are arranged perpendicular to the plane of the sheet; the hydrophobic amino acids are oriented toward the interior of the sandwich, and the hy-drophilic amino acids face outward.

The two p sheets within an immunoglobulin fold are stabilized by the hydrophobic interactions between them and by the conserved disulfide bond. An analogy has been made to two pieces of bread, the butter between them, and a toothpick holding the slices together. The bread slices represent the two p pleated sheets; the butter represents the hydrophobic interactions between them; and the toothpick represents the intrachain disulfide bond. Although variable and constant domains have a similar structure, there are subtle differences between them. The V domain is slightly longer than the C domain and contains an extra pair of p strands within the p-sheet structure, as well as the extra loop sequence connecting this pair of p strands (see Figure 4-7).

The basic structure of the immunoglobulin fold contributes to the quaternary structure of immunoglobulins by facilitating noncovalent interactions between domains

Structure Immunoglobulin Fold

Structural formula of a p pleated sheet containing two antiparallel p strands. The structure is held together by hydrogen bonds between peptide bonds of neighboring stretches of polypeptide chains. The amino acid side groups (R) are arranged perpendic ular to the plane of the sheet. [Adapted from H. Lodish et al., 1995, Molecular Cell Biology, 4th ed., Scientific American Books, New York; reprinted by permission of W. H. Freeman and Company.]

FIGURE 4-4

Structural formula of a p pleated sheet containing two antiparallel p strands. The structure is held together by hydrogen bonds between peptide bonds of neighboring stretches of polypeptide chains. The amino acid side groups (R) are arranged perpendic ular to the plane of the sheet. [Adapted from H. Lodish et al., 1995, Molecular Cell Biology, 4th ed., Scientific American Books, New York; reprinted by permission of W. H. Freeman and Company.]

Immunoglobulin Domain

FIGURE 4-5

Ribbon representation of an intact monoclonal antibody depicting the heavy chains (yellow and blue) and light chains (red). The domains of the molecule composed of p pleated sheets are readily visible as is the extended conformation of the hinge re gion. [The laboratory of A. McPherson provided this image, which is based on x-ray crystallography data determined by L. J. Harris et al., 1992, Nature 360:369. The image was generated using the computer program RIBBONS.]

across the faces of the p sheets (Figure 4-8). Interactions form links between identical domains (e.g., CH2/CH2, Ch3/Ch3, and CH4/CH4) and between nonidentical domains (e.g., VH/VL and CH1/CL). The structure of the im-munoglobulin fold also allows for variable lengths and sequences of amino acids that form the loops connecting the p strands. As the next section explains, some of the loop sequences of the VH and VL domains contain variable amino acids and constitute the antigen-binding site of the molecule.

Antigen binding

Antigen binding

Antigen Multiple Domains

Biological activity

Biological activity

No hinge region

Additional domain

No hinge region

Additional domain

FIGURE 4-6

(a) Heavy and light chains are folded into domains, each containing about 110 amino acid residues and an intrachain disulfide bond that forms a loop of 60 amino acids. The amino-terminal domains, corresponding to the V regions, bind to antigen;

effector functions are mediated by the other domains. (b) The ^ and € heavy chains contain an additional domain that replaces the hinge region.

CL domain

VL domain Loops

ß strands

CL domain

VL domain Loops

ß strands

Cdr Immunoglobulin
CDRs

ß-strand arrangement

Immunoglobulin Fold

CDRs

CDRs (complementarity-determining regions). Heavy-chain domains have the same characteristic structure. (b) The p pleated sheets are opened out to reveal the relationship of the individual p strands and joining loops. Note that the variable domain contains two more p strands than the constant domain. [Part (a) adapted from M. Schiffer et al, 1973, Biochemistry 12:4620; reprinted with permission; part (b) adapted from Williams and Barclay, 1988, Annu. Rev. Immunol. 6:381.]

CDRs

FIGURE 4-7

(a) Diagram of an immunoglobulin light chain depicting the immunoglobulin-fold structure of its variable and constant domains. The two ß pleated sheets in each domain are held together by hydrophobic interactions and the conserved disulfide bond. The ß strands that compose each sheet are shown in different colors. The amino acid sequences in three loops of each variable domain show considerable variation; these hypervariable regions (blue) make up the antigen-binding site. Hypervariable regions are usually called

CDRs (complementarity-determining regions). Heavy-chain domains have the same characteristic structure. (b) The p pleated sheets are opened out to reveal the relationship of the individual p strands and joining loops. Note that the variable domain contains two more p strands than the constant domain. [Part (a) adapted from M. Schiffer et al, 1973, Biochemistry 12:4620; reprinted with permission; part (b) adapted from Williams and Barclay, 1988, Annu. Rev. Immunol. 6:381.]

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  • ANNI
    Where are CDR regions on IgG molecule?
    8 years ago

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