A continued Introduction to the elementary Setup of our Immune System #3

Visualization of Immunoglobulin G (IgG) - Image Source

The following proteins are involved in our immune response:

• Immunoglobulins
• MHC
• T cell receptors

Structural resemblance suggests that these proteins do have a single common ancestor. The X-ray structure was first solved for immunoglobulin, therefore the fold
(depicted in the first image) is called the "Immunoglobulin Fold".
As shown in the next image, the basic structure consists of two identical light and heavy chains, which are linked to each other by disulfide bonds.

There are two classes of light chains (named λ and κ) with no functional difference between them and five different isotypes of heavy chains, which divide the immunoglobulins (Igs) into different functional classes: IgG, IgD, IgE, IgA, IgM

Image Source
These classes do have different effector properties in the elimination of antigens. Each class of heavy chains can combine with either of the two classes of light chains. The ones with the simplest structure are IgGs, which are also the major class of human immunoglobulins.
A sequence comparison of IgGs shows that the N-terminal domain of each of the polypeptides contributing to the overall structure is highly variable whereas the other domain towards the C-terminus remains constant.
Hence a light chain comprises one variable domain (VL) and one constant domain (CL) though the heavy chain contains one variable domain (VH) and three constant domains (CH1, CH2, CH3). → see images

The variable domains are not uniformly variable but contain three areas of hypervariability, also called the "Complementarity Determining Regions" or short CDR1-3. These are the regions that determine the specificity of the antigen-antibody interaction.
Due to the conformational flexibility of the hinge region in the heavy chain, crystallisation of an entire Ig proved impossible. Digestion with papain, which cleaves the heavy chain in the hinge region, generates two fragments:

• Fab (Fragment, antigen binding)
• Fc (Fragment, crystallizes easily)

Thus it was possible to obtain further structural information on immunoglobulins:

The Immunoglobulin Fold

All constant domains consist of seven β- strands arranged in two anti-parallel sheets (blue and green). The sheets are closely packed against each other, are linked by a disulfide bridge between strand F in the three-stranded sheet and strand B in the four-stranded sheet and their overall arrangment can be described as a Greek Key Barrel - motif.

In the constant domains the loops are short and their sequence is invariant, latter also applies for the residues in the β-sheets (arrows).

Comparison to the variable domain

The overall structure of the variable domain is similar to the constant domain. There are only a few differences: Two additional strands are inserted into the loop region connecting strand C and D, hence there are nine instead of seven ß-strands. These two additional strands are important since they provide the hypervariable region CDR2. Two of the other loops are elongated and present the hypervariable regions CDR1 and CDR3. All three loops involved in the antigen recognition and binding are clustered together at one end of the β-sheets.

The variable domains of Igs are an excellent example of the principle that functional residues are frequently provided by loop regions attached to a stable structural framework.
The variable domain of the light (VL) and heavy (VH) chain associate with each other, giving all hypervariable regions close together at one end of the immunoglobulin. Likewise, CL and CH1 form tight and extensive contacts providing structural stability for the overall system. The constant domains associate mainly by hydrophobic interactions between the four-stranded ß-sheets in both CL and CH1.
. . .
The two variable domains are associated with each other in a strikingly different mode. If they were packed as the constant domains, the hypervariable areas would be to far away to generate an antigen binding site. In the variable domain, the two 5-stranded β-sheets form the domain-domain interaction area like shown in the following illustration:

The 5-stranded β-sheets have a curvature which results in the formation of a half-barrel. The two sheets associate such that they form a barrel structure of eight β-strands (as shown above) with the hypervariable regions at one end of the barrel structure.
Depending on the antigen, the six hypervariable loops of the two variable chains can create either flat surfaces (for binding of a large protein surface, an "epitope") or they
can generate deep crevices to bind a small molecule, a "hapten".

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mountain.phil28

References:
Information and non-direct-cited images are taken from
"Molecular Physiology" lectures at the TU Graz.