Crystal structure of the CD2-binding domain of CD58 (lymphocyte function-associated antigen 3) at 1.8-Å resolution
Ikemizu S, Sparks LM, van der Merwe PA, Harlos K, Stuart DI, Jones EY, Davis SJ. (1999), Proc Natl Acad Sci U S A. 96, 4289-94
The binding of the cell surface molecule CD58 (formerly lymphocyte function-associated antigen 3) to its ligand, CD2, significantly increases the sensitivity of antigen recognition by T cells. This was the first heterophilic cell adhesion interaction to be discovered and is now an important paradigm for analyzing the structural basis of cell-cell recognition. The crystal structure of a CD2-binding chimeric form of CD58, solved to 1.8-Å resolution, reveals that the ligand binding domain of CD58 has the expected Ig superfamily V-set topology and shares several of the hitherto unique structural features of CD2, consistent with previous speculation that the genes encoding these molecules arose via duplication of a common precursor. Nevertheless, evidence for considerable divergence of CD2 and CD58 is also implicit in the structures. Mutations that disrupt CD2 binding map to the highly acidic surface of the AGFCC’C” beta-sheet of CD58, which, unexpectedly, lacks marked shape complementarity to the equivalent, rather more basic CD58-binding face of human CD2. The specificity of the very weak interactions of proteins mediating cell-cell recognition may often derive largely from electrostatic complementarity, with shape matching at the protein-protein interface being less exact than for interactions that combine specificity with high affinity, such as those involving antibodies.
Properties of the ligand binding faces of CD58 (A–D, G, and H) and human CD2 (E and F) viewed as in Fig. 3 A and B, respectively. In A and E, the GRASP (22) surfaces of residues whose mutation disrupts or has no effect on binding are colored red and are labeled or are colored green, respectively (only a subset of the mutated human CD2 residues are labeled in E for clarity). In B and F, the electrostatic potential calculated at neutral pH is shown projected onto the GRASP surfaces of the two domains; blue represents positive potential, white represents neutral, and red represents negative potential contoured at ±8.5 kT. In C, D, G, and H, the electrostatic potential of the ligand binding surface of human CD2, contoured at ±2.5 kT after docking with CD58, is shown projected onto the GRASP surface of CD58 domain 1. The models used to dock the proteins are the homodimeric human sCD2 (9) (C) and rat sCD2 [molecule 2 of the asymmetric unit (8) (D)] crystal lattice contacts, the homodimeric interaction of CD8 monomers (27) (G), and the putative, membrane-spanning homodimeric interaction of P0 monomers (28) (H). Red and blue arrows in the lower right hand corners of C, D, G, and H indicate the relative orientations of the C β-strands of the domain 1 AGFCC′C′′ sheets of CD58 and CD2, respectively, in each of the four model complexes. In C and D, the projected electrostatic surface of CD2 is highly complementary to that of CD58 shown in B.