Davis S J, Davies E A, Tucknott M G, Jones E Y, van der Merwe P A
Molecular Sciences Division, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom.
Proc Natl Acad Sci U S A. 1998 May 12;95(10):5490-4. doi: 10.1073/pnas.95.10.5490.
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.
对蛋白质-蛋白质识别结构基础的深入了解主要来自对抗体、激素受体和蛋白酶等蛋白质的分析，这些蛋白质以相对较高的亲和力（Ka约为10⁹ M⁻¹）结合其配体。相比之下，对介导细胞黏附和细胞-细胞识别的极低亲和力相互作用的研究较少。作为蛋白质-蛋白质识别位点，T淋巴细胞细胞-细胞识别分子CD2的配体结合面与抗体和蛋白酶相比，与其配体的结合能力弱10⁴至10⁵倍，它既非常平坦又带大量电荷，这一点很不寻常。对突变和离子强度对CD2与其配体CD48结合的影响分析表明，这些带电荷的残基对这种相互作用的结合能贡献很小，如果有的话。然而，这些带电荷残基的缺失被证明会显著降低配体结合特异性。因此，带电荷的残基增加了CD2结合的特异性而不增加亲和力。这种现象可能是由于带电荷结合表面之间需要静电互补，以补偿结合时与带电荷残基相互作用的水的去除。有人提出，这种识别模式非常适合需要低亲和力的生物相互作用，因为它将特异性的增加与亲和力的增加分离开来。
