Evolution of proteins formed by beta-sheets. II. The core of the immunoglobulin domains.

We have analysed and compared the structures of 11 immunoglobulin domains available from high-resolution crystal-structure determinations. These include examples of the domain classes Vκ, Vλ, Vγ, Cλ, Cγ1, Cγ2 and Cγ3. The core of the structure of each of the 11 domains is formed by a set of 35 or 36 homologous residues that form two β-sheets packed face-to-face. Only three residues are common to all domains: two cysteines that form a disulphide bridge between the β-sheets. and a tryptophan that packs against them. The other interior residues tend to retain Hydrophobic character but vary greatly in size (the mean variation is 60 A3) and shape. We examined how the interface between the β-sheets accommodates these mutations. We describe examples of the following mechanisms. 1. (1) Displacements and rotations of the β-sheets relative to each other by up to 2 A and 20 °. 2. (2) Lateral insertion of side-chains from external loops into the interface region, to compensate for reductions in the volume of β-sheet residues. 3. (3) Insertion of a residue into a strand to form a β-bulge. 4. (4) Local changes in conformation. 5. (5) Only rarely, complementarity in adjacent mutations. Although certain of these mechanisms are specific to the double β-sheet structure, the immunoglobulin domains like other families of proteins, accommodate mutations of interior residues through substantial structural changes consistent with the preservation of their function.