Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Campus, London SE1 1UL, United Kingdom.
J Biol Chem. 2012 Sep 7;287(37):31457-61. doi: 10.1074/jbc.C112.397059. Epub 2012 Jul 19.
IgE, the antibody that mediates allergic responses, acts as part of a self-regulating protein network. Its unique effector functions are controlled through interactions of its Fc region with two cellular receptors, FcεRI on mast cells and basophils and CD23 on B cells. IgE cross-linked by allergen triggers mast cell activation via FcεRI, whereas IgE-CD23 interactions control IgE expression levels. We have determined the CD23 binding site on IgE, using a combination of NMR chemical shift mapping and site-directed mutagenesis. We show that the CD23 and FcεRI interaction sites are at opposite ends of the Cε3 domain of IgE, but that receptor binding is mutually inhibitory, mediated by an allosteric mechanism. This prevents CD23-mediated cross-linking of IgE bound to FcεRI on mast cells and resulting antigen-independent anaphylaxis. The mutually inhibitory nature of receptor binding provides a degree of autonomy for the individual activities mediated by IgE-FcεRI and IgE-CD23 interactions.
IgE 是介导过敏反应的抗体，作为自我调节蛋白质网络的一部分。它的独特效应功能通过其 Fc 区域与两个细胞受体的相互作用来控制，即肥大细胞和嗜碱性粒细胞上的 FcεRI 和 B 细胞上的 CD23。过敏原交联的 IgE 通过 FcεRI 触发肥大细胞激活，而 IgE-CD23 相互作用控制 IgE 的表达水平。我们使用 NMR 化学位移映射和定点突变相结合的方法确定了 IgE 上的 CD23 结合位点。我们表明，CD23 和 FcεRI 结合位点位于 IgE 的 Cε3 结构域的两端，但受体结合是相互抑制的，由变构机制介导。这可以防止与肥大细胞上的 FcεRI 结合的 IgE 介导的 CD23 交联，从而防止抗原非依赖性过敏反应。受体结合的相互抑制性质为 IgE-FcεRI 和 IgE-CD23 相互作用介导的个体活性提供了一定程度的自主性。
