Hibbs M L, Tolvanen M, Carpén O
Center for Blood Research, Harvard Medical School, Boston, MA 02115.
J Immunol. 1994 May 1;152(9):4466-74.
Ag-Ab complexes are cleared from the circulation through a complex system of receptors for the Fc portion of Ig (FcRs). Fc gamma RIII (CD16) is a low affinity FcR for IgG that is composed of two highly homologous Ig-like extracellular domains. Using secondary structure predictions, we located a strongly hydrophilic region in the second Ig-like domain of Fc gamma RIII that is predicted to lie between beta-strands C and C'. Substitutions of seven out of eight amino acids in this region abolished binding to IgG. Substitution of a conformationally adjacent amino acid in a bend just before beta-strand F and an amino acid in the B-C loop also affected ligand binding. However, amino acid substitutions in two different predicted loops in the second Ig-like domain as well as substitutions to three predicted loops in the first Ig-like domain had no effect on function. A chimeric Fc gamma RIII molecule lacking the second Ig-like domain was unable to bind IgG further, suggesting the presence of the binding site in the second domain. Neutralizing mAbs that inhibit Fc gamma RIII interaction with IgG were mapped to the E-F loop in the membrane proximal domain of Fc gamma RIII, providing further evidence of the importance of this region of the molecule in ligand interaction.
抗原-抗体复合物通过免疫球蛋白（Ig）Fc段的复杂受体系统从循环中清除。FcγRIII（CD16）是一种对IgG亲和力较低的Fc受体，由两个高度同源的Ig样细胞外结构域组成。利用二级结构预测，我们在FcγRIII的第二个Ig样结构域中定位到一个强亲水区域，该区域预计位于β链C和C'之间。该区域八个氨基酸中的七个被替换后，与IgG的结合消失。在β链F之前的一个弯曲处的一个构象相邻氨基酸和B-C环中的一个氨基酸被替换也影响配体结合。然而，第二个Ig样结构域中两个不同预测环中的氨基酸替换以及第一个Ig样结构域中三个预测环中的替换对功能没有影响。一个缺少第二个Ig样结构域的嵌合FcγRIII分子不能再结合IgG，这表明结合位点存在于第二个结构域中。抑制FcγRIII与IgG相互作用的中和单克隆抗体被定位到FcγRIII膜近端结构域的E-F环，这进一步证明了该分子区域在配体相互作用中的重要性。
