Diversity in the Variable Region Domain Is Concentrated in CDRs

Detailed comparisons of the amino acid sequences of a large number of VL and VH domains revealed that the sequence variation is concentrated in a few discrete regions of these domains. The pattern of this variation is best summarized by a quantitative plot of the variability at each position of the polypeptide chain. The variability is defined as:

# of different amino acids at a given position

Variability = -

Frequency of the most common amino acid at given position

Thus if a comparison of the sequences of 100 heavy chains revealed that a serine was found in position 7 in 51 of the sequences (frequency 0.51), it would be the most common amino acid. If examination of the other 49 sequences showed that position 7 was occupied by either glutamine, histidine, proline, or tryptophan, the variability at that position would be 9.8 (5/0.51). Variability plots ofVL and VH domains of human antibodies show that maximum variation is seen in those portions of the sequence that correspond to the loops that join the p strands (Figure 4-9). These regions were originally called hypervariable regions in recognition of their high variability. Hypervariable regions form the antigen-binding site of the antibody molecule. Because the antigen binding site is complementary to the structure of the epitope,

Antigen-binding site

VH domain

VH domain

Antigen-binding site

Hypervariable Regions

Antigen-binding site

Heavy chains

Antigen-binding site

Heavy chains ch3

Hypervariable Regions
Carbohydrate

FIGURE 4-8

Interactions between domains in the separate chains of an immunoglobulin molecule are critical to its quaternary structure. (a) Model of IgG molecule, based on x-ray crystallographic analysis, showing associations between domains. Each solid ball represents an amino acid residue; the larger tan balls are carbohydrate. The two light chains are shown in shades of red; the two heavy chains, in shades of blue. (b) A schematic diagram showing the in teracting heavy- and light-chain domains. Note that the CH2/CH2 domains protrude because of the presence of carbohydrate (tan) in the interior. The protrusion makes this domain more accessible, enabling it to interact with molecules such as certain complement components. [Part (a) from E. W. Silverton et al., 1977, Proc. Nat. Acad. Sci. U.S.A. 74:5140.]

these areas are now more widely called complementarity determining regions (CDRs). The three heavy-chain and three light-chain CDR regions are located on the loops that connect the p strands of the VH and VL domains. The remainder of the VL and VH domains exhibit far less variation; these stretches are called the framework regions (FRs). The wide range of specificities exhibited by antibodies is due to variations in the length and amino acid sequence of the six CDRs in each Fab fragment. The framework region acts as a scaffold that supports these six loops. The three-dimensional structure of the framework regions of virtually all antibodies analyzed to date can be superimposed on one another; in contrast, the hypervariable loops (i.e., the CDRs) have different orientations in different antibodies.

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