Crystal structure and binding properties of the CD2 and CD244 (2B4)-binding protein, CD48
Evans EJ, Castro MA, O’Brien R, Kearney A, Walsh H, Sparks LM, Tucknott MG, Davies EA, Carmo AM, van der Merwe PA, Stuart DI, Jones EY, Ladbury JE, Ikemizu S, Davis SJ. (2006), J Biol Chem. 281, 29309-20
The structural analysis of surface proteins belonging to the CD2 subset of the immunoglobulin superfamily has yielded important insights into transient cellular interactions. In mice and rats, CD2 and CD244 (2B4), which are expressed predominantly on T cells and natural killer cells, respectively, bind the same, broadly expressed ligand, CD48. Structures of CD2 and CD244 have been solved previously, and we now present the structure of the receptor-binding domain of rat CD48. The receptor-binding surface of CD48 is unusually flat, as in the case of rat CD2, and shares a high degree of electrostatic complementarity with the equivalent surface of CD2. The relatively simple arrangement of charged residues and this flat topology explain why CD48 cross-reacts with CD2 and CD244 and, in rats, with the CD244-related protein, 2B4R. Comparisons of modeled complexes of CD2 and CD48 with the complex of human CD2 and CD58 are suggestive of there being substantial plasticity in the topology of ligand binding by CD2. Thermodynamic analysis of the native CD48-CD2 interaction indicates that binding is driven by equivalent, weak enthalpic and entropic effects, in contrast to the human CD2-CD58 interaction, for which there is a large entropic barrier. Overall, the structural and biophysical comparisons of the CD2 homologues suggest that the evolutionary diversification of interacting cell surface proteins is rapid and constrained only by the requirement that binding remains weak and specific.
Key figure: The structure of cCD48
A, two orthogonal views of schematic α-carbon representations of cCD48 (green), cCD58 (red), and rCD2 (blue), superimposed on domain 2 of each molecule. The first residue of domain 2 in each molecule (Glu-104 in cCD48, Glu-94 in cCD58, and Glu-99 in rCD2) is marked with a green sphere. B, the inter-domain contact region is shown enlarged for cCD48 and cCD58 with key non-linker interface residues drawn as ball and stick models. rCD2 is not shown because its interactions are similar to those of cCD58. The hydrogen bonds between the two IgSF domains of cCD48 are marked as dark blue dashed lines.