There are five classes of immunoglobulins: (i) immunoglobulin G (IgG), (ii) immunoglobulin M (IgM), (iii) immunoglobulin A (IgA), (iv) immunoglobulin E (IgE), and (v) immunoglobulin D (IgD). Myeloma proteins were first used for the amino acid sequencing of immunoglobulins. These proteins were also the first immunoglobulins that were subjected to crystallographic studies. They provided the first glimpses of the domain struc-ture of the prototypic immunoglobulin.
Structure of Immunoglobulins
Immunoglobulins show the following properties:
· They are glycoproteins.
· They are a complex structure of four polypeptide chains: two identical heavy (typically 55 kDa each) chains and two identical light chains (25 kDa each). This gives immuno-globulin an overall ‘Y’ or ‘T’ shape, which is the most widely recognized feature of immunoglobulin structure.
The terms “heavy” and “light” refer to the molecular weights of the chains. The heavy chains have a molecu-lar weight of 50,000–70,000 Da, while light chains have a molecular weight of 25,000 Da. The heavy chains are longer, and light chains are shorter (Fig. 13-1).
An immunoglobulin molecule has two heavy chains. Each heavy chain is made up of 420–440 amino acids. The two heavy chains are held together by one to five disulfide (S—S) bonds. Each heavy chain is bound to a light chain by a disulfide bond and by noncovalent bonds, such as salt linkages, hydrogen bonds, and hydrophobic bonds to form a heterodimer (H–L). Similar noncovalent interactions and disulfide bridges link the two identical heavy and light (H–L) chains to each other to form the basic four-chain (H–L)2 antibody structure.
The heavy chains of a given antibody molecule determine the class of that antibody. For example, IgM contains mu ( ), IgG contains gamma ( ), IgA contains alpha ( ), IgD contains delta ( ), and IgE contains epsilon ( ) heavy chains (Table 13-1). These heavy chains are structurally and antigenically distinct for each class of immunoglobulin. They differ in their size, car-bohydrate content, and as antigens.
An immunoglobulin molecule has two light chains. Each light chain is made up of 220–240 amino acids. Light chain is attached to the heavy chain by a disulfide bond. The light chains are structurally and chemically similar in all classes of immunoglobulins. They are of two types: kappa ( ) and lambda ( ). These two types differ in their amino acids present in constant regions. Each immunoglobulin has either two or two chains but never both. The and chains are present in human serum in a ratio of 2:1.
Each polypeptide chain of an immunoglobulin molecule con-tains an amino terminal part and a carboxy terminal part. The amino terminal part is called the variable region (V region) and the carboxy terminal part is called the constant region (C region).
Both heavy and light chains contain variable and constant regions. These regions are composed of three-dimensional folded structures with repeating segments, which are called domains. Each heavy chain consists of one variable (VH) and three constant (CH) domains. IgG and IgA have three CH domains (CH1, CH2, and CH3), whereas IgM and IgE have four domains (CH1, CH2, CH3, and CH4). Each light chain consists of one variable (VL) and one constant domain (CL).
Variable region: The amino-terminal half of the light or heavychain, consisting of 100–110 amino acids, is known as vari-able or V regions (VL in light chains and VH in heavy chains). V region is different for each class of immunoglobulin.
The variable regions of both light and heavy chains consist of three highly variable regions known as hypervariable regions. The antigen combining sites Fab of the antibody molecule that consists of only 5–10 amino acids each are present in the hypervariable region of both the light and heavy chains. These antigen-binding sites are responsible for specific bind-ing of antibodies with antigens. The high specificity of anti-bodies is primarily due to the presence of these hypervariable regions.
Constant region: The carboxyl-terminal half of the moleculeis called the constant (C) region. It consists of two basic amino acid sequences. The Fc fragment, found to crystallize under low ionic conditions, is present in the constant region of heavy chain.
The constant region of the heavy chain has many biological functions. It is responsible for activation of the complement, binding to cell surface receptors, placental transfer, and many other biological activities.
The constant region of the light chain has no biological function.
A single antibody molecule has two identical heavy chains and two identical light chains, H2L2, or a multiple (H2L2)n of this basic four-chain structure. Subisotypes exist for and chains, and this leads to the existence of subclasses of the respective immunoglobulins.