The second important feature is that the amino-terminal amino acid sequences of the heavy and light chains vary greatly between different antibodies. The variability is limited to approximately the first 110 amino acids, corresponding to the first Ig domain, whereas the remaining domains are constant between immunoglobulin chains of the same isotype. The amino-terminal variable Ig domains (V domains) of the heavy and light chains (VH and VL, respectively) together make up the V region of the antibody and determine its antigen-binding specificity, whereas the constant Ig domains (C domains) of the heavy and light chains (CH and CL, respectively) make up the C region (see Fig. 4.1). The multiple heavy-chain C domains are numbered from the amino-terminal end to the carboxy terminus, for example, CH1, CH2, and so on.
4-3 The domains of an immunoglobulin molecule have similar structures.
Immunoglobulin heavy and light chains are composed of a series of Ig domains that have a similar overall structure. Within this basic structure, there are distinct differences between V and C domains that are illustrated for the light chain in Fig. 4.3. Each V or C domain is constructed from two β sheets. A β sheet is
Fig. 4.3 The structure of immunoglobulin constant and variable domains. The upper panels show schematically the folding pattern of the constant (c) and variable (V) domains of an immunoglobulin light chain. each domain is a barrel-shaped structure in which strands of polypeptide chain (β strands) running in opposite directions (antiparallel) pack together to form two β sheets (shown in yellow and green for the c domain and red and blue for the V domain), which are held together by a disulfide bond. The way in which the polypeptide chain folds to give the final structure can be seen more clearly when the sheets are opened out, as shown in the lower panels. The β strands are lettered sequentially with respect to the order of their occurrence in the amino acid sequence of the domains; the order in each β sheet is characteristic of immunoglobulin domains. The β strands cʹ and cʹʹ that are found in the V domains but not in the c domains are indicated by a blue-shaded background. The characteristic four-strand plus three-strand (c-region type domain) or four-strand plus five-strand (V-region type domain) arrangements are typical immunoglobulin superfamily domain building blocks, found in a whole range of other proteins as well as antibodies and T-cell receptors.
built from several β strands, which are regions of protein where several consecutive polypeptides have their peptide backbone bonds arranged in an extended, or flat, conformation. β strands in proteins are sometimes shown as ‘ribbons with an arrow’ to indicate the direction of the polypeptide backbone (see Fig. 4.3). β strands can pack together in a side-by-side manner, being stabilized laterally by two or three backbone hydrogen bonds between adjacent strands. This arrangement is called a β sheet. The Ig domain has two β sheets that are folded onto each other, like two pieces of bread, into a structure called a β sandwich, and are covalently linked by a disulfide bond between cysteine residues from each β sheet. This distinctive structure is known as the immunoglobulin fold.
The similarities and differences between V and C domains can be seen in the bottom panels of Fig. 4.3. Here, the Ig domains have been opened out to show how their respective polypeptide chains fold to create each of the βsheets and how each polypeptide chain forms flexible loops between adjacent β strands as it turns to change direction. The main difference between the V and C domains is that the V domain is larger and contains extra β strands, called Cʹ and Cʹʹ. In the V domain, the flexible loops formed between some of the β strands contribute to the antigen-binding site of the immunoglobulin molecule.