Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA 50011, USA.
Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA 50011, USA.
Structure. 2014 Oct 7;22(10):1478-88. doi: 10.1016/j.str.2014.08.002. Epub 2014 Sep 4.
Immunoglobulin G1 (IgG1)-based therapies are widespread, and many function through interactions with low-affinity Fc γ receptors (FcγR). N-glycosylation of the IgG1 Fc domain is required for FcγR binding, though it is unclear why. Structures of the FcγR:Fc complex fail to explain this because the FcγR polypeptide does not bind the N-glycan. Here we identify a link between motion of the N-glycan and Fc:FcγRIIIa affinity that explains the N-glycan requirement. Fc F241 and F243 mutations decreased the N-glycan/polypeptide interaction and increased N-glycan mobility. The affinity of the Fc mutants for FcγRIIIa was directly proportional to the degree of glycan restriction (R(2) = 0.82). The IgG1 Fc K246F mutation stabilized the N-glycan and enhanced affinity for FcγRIIIa. Allosteric modulation of a protein/protein interaction represents a previously undescribed role for N-glycans in biology. Conserved features suggesting a similar N-glycan/aromatic interaction were also found in IgD, IgE, and IgM, but not IgA.
免疫球蛋白 G1（IgG1）为基础的治疗方法应用广泛，许多方法通过与低亲和力 Fcγ 受体（FcγR）相互作用来发挥作用。IgG1 Fc 结构域的 N-糖基化是 FcγR 结合所必需的，但不清楚原因是什么。FcγR：Fc 复合物的结构无法解释这一点，因为 FcγR 多肽不结合 N-聚糖。在这里，我们确定了 N-聚糖运动与 Fc：FcγRIIIa 亲和力之间的联系，从而解释了 N-聚糖的需求。Fc F241 和 F243 突变降低了 N-聚糖/多肽相互作用并增加了 N-聚糖的迁移率。Fc 突变体与 FcγRIIIa 的亲和力与糖基化限制的程度成正比（R(2) = 0.82）。IgG1 Fc K246F 突变稳定了 N-聚糖并增强了与 FcγRIIIa 的亲和力。蛋白质/蛋白质相互作用的变构调节代表了 N-聚糖在生物学中以前未被描述的作用。在 IgD、IgE 和 IgM 中也发现了保守的特征，表明存在类似的 N-聚糖/芳香族相互作用，但 IgA 中不存在。
