It is a type of globulin.
It is named because it appears last when proteins are separated from the blood serum by electrophoresis.
The term gammaglobulin is often used as a synonym for immunoglobulin, because most immunoglobulins are gamma globulins; however, since some immunoglobulins migrate to the beta or alpha regions, the term tends to be used less.
Immunoglobulins are heterodimeric proteins composed of two heavy chains (H) and two light chains (L). They can be functionally separated into variable domains (V) that bind to antigens and constant domains (C) that specify effector functions such as complement activation or binding to Fc receptors.
The variable domains are created by a complex series of gene rearrangement events, and then can undergo somatic hypermutation after exposure to the antigen to allow affinity maturation.
Each V domain can be divided into three regions of sequence variability, termed complementarity determining regions, or CDR, and four regions of relatively constant sequence called framework regions, or FR.
The three CDRs of the H chain combine with the three CDRs of the L chain to form the antigen binding site, as it is classically defined. There are five main classes of heavy chain C domains.
Each class defines the isotypes IgM, IgG, IgA, IgD and IgE. IgG can be divided into four subclasses, IgG1, IgG2, IgG3 and IgG4, each with its own biological properties; and IgA can be divided similarly into IgA1 and IgA2.
The constant domains of the H chain can be changed to allow altered effector function while maintaining the specificity of the antigen.
More than 100 years of research on the structure and function of gamma globulin have only served to emphasize the complex nature of this protein. Typically, the receptors join a limited and defined set.
However, although individual gamma globulin also binds to a limited and defined set of ligands, immunoglobulins as a population can bind to a virtually unlimited array of antigens that share little or no similarity.
This adjustable binding property depends on a complex series of mechanisms that alter the DNA of individual B cells.
Gammaglobulin also serves two purposes:
- Cell surface receptors for the antigen that allows cell signaling.
- Cell activation and that of soluble effector molecules that can bind and neutralize antigens individually at a distance.
Structure of gamma globulin
The antibody molecules (or gamma globulins) are glycoproteins composed of one or more units, each with four polypeptide chains; two identical heavy chains (H) and two identical light chains (L).
The amino terminal ends of the polypeptide chains show considerable variation in amino acid composition and are referred to as variable regions (V) to distinguish them from relatively constant regions (C).
Each L string consists of a variable domain, VL and a constant domain, CL. The H chains consist of a variable domain, VH and three constant domains CH1, CH2 and CH3.
Each heavy chain has approximately twice the amino acid and molecular weight (~50,000) as each light chain (~ 25,000), resulting in a molecular weight of the total immunoglobulin monomer of about 150,000.
The heavy and light chains are held together by a combination of non-covalent interactions and covalent interchain disulfide bonds, forming a bilateral symmetric structure.
The V regions of the H and L chains comprise the antigen-binding sites of the immunoglobulin (Ig) molecules. Each Ig monomer contains two antigen-binding sites and is said to be bivalent.
The hinge region is the area of the H chains between the first and the second domain of the C region and is held together by disulfide bonds. This flexible hinge region (found in IgG, IgA and IgD, but not IgM or IgE) allows the distance between the two antigen-binding sites to vary.
Classes of gammaglobulins
The five major classes of gammaglobulin are IgG, IgM, IgA, IgD and IgE. These are distinguished by the type of heavy chain found in the molecule.
IgG molecules have heavy chains known as gamma chains; IgM have mu chains; IgAs have alpha chains; IgE have epsilon chains; and IgD have delta chains.
Differences in heavy chain polypeptides allow these gamma globulins to function in different types of immune responses and at particular stages of the immune response.
The sequences of polypeptide proteins responsible for these differences are found mainly in the Fc fragment. While there are five different types of heavy chains, there are only two major types of light chains: kappa (κ) and lambda (λ).
Antibody classes differ in valence as a result of different numbers of Y-like units (monomers) that bind to form the complete protein.
For example, in humans, functioning IgM antibodies have five Y-units (pentamer) containing a total of 10 light chains, 10 heavy chains and 10 antigen binding.
In addition to the major classes of gammaglobulins, there are several subclasses of Ig in all members of a particular animal species.
The antibodies are classified into subclasses according to the minor differences in the heavy chain type of each Ig class. In humans there are four subclasses of IgG: IgG1, IgG2, IgG3 and IgG4 (numbered in order of decreasing concentration in serum).
The variance between the different subclasses is less than the variance between the different classes. For example, IgG1 is more closely related to IgG2, IgG3 and IgG4 than to IgA, IgM, IgD or IgE.
Consequently, antibody-binding proteins (eg, Protein A or Protein G) and most secondary antibodies used in immunodetection methods cross-react with multiple subclasses but generally not with multiple Ig classes.
Polyclonal and monoclonal antibodies
Antibodies (whatever their class or subclass) are produced and purified in two basic forms for use as reagents in immunoassays: polyclonal and monoclonal.
Typically, the immunological response to an antigen is heterogeneous, resulting in many different cell lines of B lymphocytes (plasma cell precursors) that produce antibodies against the same antigen.
All these cells originate from common stem cells, but each develops the individual ability to produce an antibody that recognizes a particular determinant (epitope) in the same antigen.
As a consequence of this heterogeneous response, the serum of an immunized animal will contain numerous clones of antigen-specific antibodies, potentially of several different classes of gammaglobulins and subclasses that generally comprise from 2 to 5% of the total immunoglobulin.
Because it contains this heterogeneous collection of antigen-binding gammaglobulins, an antibody purified from said sample is called a polyclonal antibody.
Polyclonal antibodies, which are generally purified directly from the serum, are especially useful as secondary antibodies labeled in immunoassays.