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, hormone receptors, and proteases that bind their ligands with relatively high affinity (Ka approximately 10(9) M-1). In contrast, few studies have been done on the very low affinity interactions mediating cell adhesion and cell-cell recognition. As a site of protein-protein recognition, the ligand binding face of the T lymphocyte cell-cell recognition molecule, CD2, which binds its ligands 10(4)- to 10(5)-fold more weakly than do antibodies and proteases, is unusual in being both very flat and highly charged. An analysis of the effect of mutations and ionic strength on CD2 binding to its ligand, CD48, indicates that these charged residues contribute little, if any, binding energy to this interaction. However, the loss of these charged residues is shown to markedly reduce ligand-binding specificity. Thus, the charged residues increase the specificity of CD2 binding without increasing the affinity. This phenomenon is likely to result from a requirement for electrostatic complementarity between charged binding surfaces to compensate for the removal, upon binding, of water interacting with the charged residues. 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.
Davis
S J
SJ
Molecular Sciences Division, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom. sdavis@molbiol.ox.ac.uk
Davies
E A
EA
Tucknott
M G
MG
Jones
E Y
EY
van der Merwe
P A
PA
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001665:Binding Sites; D015374:Biosensing Techniques; D018801:CD2 Antigens / Q000378:metabolism*; D000071178:CD48 Antigen; D008024:Ligands; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009994:Osmolar Concentration; D011485:Protein Binding; D051381:Rats; D055672:Static Electricity; D013499:Surface Properties
D015703:Antigens, CD; D018801:CD2 Antigens; D000071178:CD48 Antigen; C000604067:Cd48 protein, rat; D008024:Ligands