Immunoglobulin Superfamily


The immunoglobulin (Ig) superfamily (IgSF) consists of a group of proteins that exploit the structural robustness and fundamental stability of the Ig fold for a wide assortment of functions across a broad span of evolutionary time, extending from microorganisms to humans. Several classification schemes, based on three‐dimensional structure or amino acid sequence patterns, have been developed to assist in understanding functional and evolutionary relationships. Although the best‐understood activities of IgSF members are related to immunological recognition, a number of related molecules participate in developmental and homeostatic phenomena. Manipulation of the IgSF by recombinant methodologies including bacteriophage and yeast display offers in vitro approaches to increase the available diversity of novel structures for almost limitless functions.

Key Concepts

  • Immunoglobulin domains can be recognised by their three‐dimensional structure and organisation of secondary structural components.
  • Common features of β‐sheet organisation and stabilisation by a disulphide bond permit sub‐classification of the immunoglobulin superfamily (IgSF) members into V, C1, C2 and I set IgSF folds.
  • Although exploited extensively for functional roles in immune recognition, such as for antibodies and T‐cell receptors (TCR), the immunoglobulin fold is also found in a wide variety of structures employed in cell–cell interactions.
  • The immunoglobulin fold offers a stable core upon which variable loops are grafted providing a scaffold for many functions.
  • Various display technologies have been used to generate high‐affinity antibodies and TCR.

Keywords: immunoglobulin fold; molecular fold; structural motif; antibodies; T‐cell receptors; immune recognition

Figure 1. Basic features of the immunoglobulin fold. (a) Schematic illustrating the Greek keymotif. Conserved β‐strands are indicated by letters A through G, beginning at the amino terminus (N) and proceeding through to the carboxyl terminus (C‐term). The definitive disulphide bond linking strand B with strand F is shown. (b) Three‐dimensional illustration depicting the β‐barrel resulting from the ‘four on three’ β sandwich. Here, the disulphide bond is not shown. (c) A ‘top view’ illustration in which each of the β‐strands, shown by a triangle, is lettered, its orientation is indicated by the upward or downward direction in which the triangle is pointing and the strand associations are indicated by the juxtaposition of the sides of the triangles. The disulphide bond connecting strands B and F is indicated by a line.
Figure 2. Schematic and ribbon diagram of C‐type Ig domains. The C1 domain is the CH domain from 1dfb. One interesting variation of this particular molecule is that the region joining the E and F strands is a short helix. The C2 domain is from the CD2 structure, 1hnf. The strand switch, in which C′ remains as part of the G, F, C and C′ layers of the sandwich rather than associating with the A, B and E layers, is apparent.
Figure 3. Schematic and ribbon illustrations of V domains. As an example, the heavy chain V region from 7Fab is illustrated. Because the C″ strand is very short in this molecule, it is not indicated in the ribbon diagram.
Figure 4. Diagram of the structure of an intact antibody. This is an illustration of the IgG2a monoclonal antibody 231 (Harris et al., ). The heavy chains are shown in cyan and blue, the light chains in red and violet. The variable heavy (VH) and variable light (VL) domains are labelled as are the constant C domain, which are labelled from the N to C termini as CH1, CH2 and CH3. The carbohydrate moiety is shown in a stick representation.


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Natarajan, Kannan, Mage, Michael G, and Margulies, David H(Apr 2015) Immunoglobulin Superfamily. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000926.pub2]