THE ROLE OF CHARGED RESIDUES MEDIATING LOW-AFFINITY PROTEIN-PROTEIN RECOGNITION AT THE CELL-SURFACE BY CD2

Insights into the structural basis of protein-protein recognition have come principally from the analysis of proteins such as antibodies, ho rmone receptors, and proteases that bind their ligands with relatively high affinity (K-a approximate to 10(9) M-1). In contrast, few studie s have been done on the very low affinity interactions mediating cell adhesion and cell-cell recognition. As a site of protein-protein recog nition, the ligand binding face of the T lymphocyte cell-cell recognit ion molecule, CD2, which binds its ligands 10(4)- to 10(5)-fold more w eakly than do antibodies and proteases, is unusual in being both very flat and highly charged. An analysis of the effect of mutations and io nic strength on CD2 binding to its ligand, CD48, indicates that these charged residues contribute little, if any, binding energy to this int eraction. However, the loss of these charged residues is shown to mark edly reduce ligand-binding specificity. Thus, the charged residues inc rease the specificity of CD2 binding without increasing the affinity. This phenomenon is likely to result from a requirement for electrostat ic complementarity between charged binding surfaces to compensate for the removal, upon binding, of water interacting with the charged resid ues, It is proposed that this mode of recognition is highly suited to biological interactions requiring a low affinity because it uncouples increases in specificity from increases in affinity.