An Introduction to
Immunoglobulin Structure

David Marcey
© 2021

I. Introduction
II. Tetramer Structure
III. The Immunoglobulin Fold
IV. Variable Region Structure
V. References


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I. Introduction

To the left is a model of an intact IgG1 immunoglobulin (Padlan, 1994), which can serve as a standard as we begin investigating the basics of immunoglobulin structure. Two identical heavy (H) chains and two identical light (L) chains combine to form this Y-shaped antibody molecule. Before discussing structural aspects of the H2L2 tetramer, let's examine the light and heavy chains separately.

The heavy chains each have four domains. The amino terminal variable domains (VH) are at the tips of the Y. These are followed by three constant domains: CH1, CH2, and the carboxy terminal CH3, at the base of the Y's stem.

A short stretch, the switch, connects the heavy chain variable and constant regions. The hinge connects CH2 plus CH3 (the Fc fragment) to the remainder of the antibody (the Fab fragments).

One Fc and two identical Fab fragments can be produced by proteolytic cleavage of the hinge in an intact antibody molecule.

The light chains are constructed of two domains, variable (VL) and constant (CL), separated by a switch.

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II. Tetramer Structure

Two disulfide bonds in the hinge region, between cys235 and cys238 pairs, unite the two heavy chains.

The light chains are coupled to the heavy chains by two additional disulfide bonds, between cys229s in the CH1 domains and cys214s in the CL domains.

Carbohydrate moieties are attached to asn306 of each CH2, generating a pronounced bulge in the stem of the Y.

The structural features discussed so far have important functional consequences. The variable regions of both the heavy and light chains, (VH) and (VL), lie at the tips of the Y, where they are positioned to stereochemically react with antigen (see below). The stem of the Y projects in a way to efficiently mediate effector functions such as the activation of complement. Its CH2 and CH3 domains bulge to facilitate interaction with effector proteins.

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III. The Immunoglobulin Fold

A. The Constant Domain Fold

Each domain in an antibody molecule has a similar structure of two beta sheets packed tightly against each other in a compressed antiparallel beta barrel. This conserved structure is termed the immunoglobulin fold. At left is an immunoglobulin fold of a CL domain containing a 3-stranded sheet packed against a 4-stranded sheet.

The fold is stabilized by hydrogen bonding between the beta strands of each sheet, by hydrophobic bonding between residues of opposite sheets in the interior, and by a disulfide bond between the sheets.

The 3-stranded sheet comprises strands C, F, and G, and the 4-stranded sheet has strands A, B, E, and D.

B. The Variable Domain Fold

The folds of variable domains have 9 beta strands arranged in two sheets of 4 and 5 strands.

The 5-stranded sheet is structurally homologous to the 3-stranded sheet of constant domains, but contains the extra strands C' and C''.

The remainder of the strands (A, B, C, D, E, F, G) have the same topology and similar structure as their counterparts in constant domain immunoglobulin folds.

A disulfide bond links strands B and F in opposite sheets, as in constant domains.

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IV. Variable Region Structure

The variable domains of both light and heavy immunoglobulin chains contain three hypervariable loops, or complementarity-determining regions (CDRs). Shown at left are the three CDRs of aVL domain (CDR1, CDR2, CDR3). These CDRs are clustered at one end of the beta barrel. The CDRs are loops that connect beta strands B-C, C'-C'', and F-G of the immunoglobulin fold (see above).

The VH and VL domains at the tips of antibody molecules are closely packed (see Tetramer Structure, above) such that the six CDRs (3 on each domain) cooperate in constructing a surface for antigen-specific binding.

This is shown at left for a monoclonal antibody (IgG1) (Fischmann, et al., 1991). Residues in all six CDR's (VL CDR1, CDR2, CDR3 and VH CDR1, CDR2, CDR3) project from the distal surface of the antibody tip, in position to recognize and bind antigen.

The residues in the CDRs vary from one immunoglobulin molecule to the next, imparting antigen specificity to each antibody. For more information on antibody binding antigenic molecules, see Antibody Recognition of Antigen.

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V. References

Fischmann, T.O., Bentley, G.A., Bhat, T.N., Boulot, G., Mariuzza, R.A., Phillips, S.E.V., Tello, D., and R.J. Poljak (1991). Crystallographic Refinement of the Three-dimensional Structure of the FabD1.3-Lysozyme Complex at 2.5-Å Resolution. J. Biol. Chem. 266: 12915-12920.

Padlan, E. (1994) Anatomy of the Antibody Molecule. Molecular Immunology 31: 169.

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