Hefty structures of IgA and IgM complexes Immunoglobulin M (IgM) and IgA are antibody isotypes that can form higher-order secretory complexes (sIgM and sIgA), which allows them to effectively bind and neutralize antigens with low-affinity repetitive epitopes, such as those found on the surface of many bacteria and viruses. The assembly and transport of these molecules is also dependent on the joining chain (J-chain) and the polymeric immunoglobulin receptor (pIgR) secretory component (SC). The architecture of these complex, multimeric structures has remained elusive. Li et al. resolved cryo–electron microscopy structures of the sIgM-Fc pentamer in complex with the J-chain and SC. Using similar techniques, Kumar et al. visualized dimeric, tetrameric, and pentameric structures of secretory sIgA-Fc interacting with the J-chain and SC. Both groups report highly similar mechanisms wherein the J-chain serves as a template for antibody oligomerization. An unanticipated, amyloid-like assembly of the oligomerized structure is present in both cases, with the J-chain conferring asymmetry for pIgR binding and transcytosis. These studies may inform structure-based engineering of these molecules for future therapeutic purposes. Science, this issue p. 1014, p. 1008 Cryo–electron microscopy structures of secretory antibody multimers uncover similar organizational mechanisms. Secretory immunoglobulin A (sIgA) represents the immune system’s first line of defense against mucosal pathogens. IgAs are transported across the epithelium, as dimers and higher-order polymers, by the polymeric immunoglobulin receptor (pIgR). Upon reaching the luminal side, sIgAs mediate host protection and pathogen neutralization. In recent years, an increasing amount of attention has been given to IgA as a novel therapeutic antibody. However, despite extensive studies, sIgA structures have remained elusive. Here, we determine the atomic resolution structures of dimeric, tetrameric, and pentameric IgA-Fc linked by the joining chain (JC) and in complex with the secretory component of the pIgR. We suggest a mechanism in which the JC templates IgA oligomerization and imparts asymmetry for pIgR binding and transcytosis. This framework will inform the design of future IgA-based therapeutics.

中文翻译：

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分泌型免疫球蛋白 A 核心的结构

IgA 和 IgM 复合物的重结构免疫球蛋白 M (IgM) 和 IgA 是抗体同种型，可以形成高级分泌复合物（sIgM 和 sIgA），这使它们能够有效地结合和中和具有低亲和力重复表位的抗原，例如那些存在于许多细菌和病毒的表面。这些分子的组装和运输也依赖于连接链（J 链）和聚合免疫球蛋白受体 (pIgR) 的分泌成分 (SC)。这些复杂的多聚体结构的架构仍然难以捉摸。李等人。解析了与 J 链和 SC 复合的 sIgM-Fc 五聚体的冷冻电子显微镜结构。使用类似的技术，Kumar 等人。与 J 链和 SC 相互作用的分泌型 sIgA-Fc 的二聚体、四聚体和五聚体结构的可视化。两组都报告了高度相似的机制，其中 J 链作为抗体寡聚化的模板。在这两种情况下都存在未预料到的淀粉样寡聚结构组装，J 链赋予 pIgR 结合和转胞吞作用的不对称性。这些研究可能会为这些分子的基于结构的工程提供信息，以用于未来的治疗目的。科学，这个问题 p。1014 页。1008 分泌性抗体多聚体的冷冻电子显微镜结构揭示了类似的组织机制。分泌性免疫球蛋白 A (sIgA) 代表免疫系统抵御粘膜病原体的第一道防线。IgAs 通过聚合免疫球蛋白受体 (pIgR) 作为二聚体和高级多聚体跨上皮运输。到达管腔一侧后，sIgAs 介导宿主保护和病原体中和。近年来，作为新型治疗性抗体的 IgA 受到越来越多的关注。然而，尽管进行了广泛的研究，sIgA 结构仍然难以捉摸。在这里，我们确定了通过连接链 (JC) 连接并与 pIgR 的分泌成分复合的二聚体、四聚体和五聚体 IgA-Fc 的原子分辨率结构。我们提出了一种机制，其中 JC 模板化 IgA 寡聚化并赋予 pIgR 结合和转胞吞作用的不对称性。该框架将为未来基于 IgA 的疗法的设计提供信息。我们确定了通过连接链 (JC) 连接并与 pIgR 的分泌成分复合的二聚体、四聚体和五聚体 IgA-Fc 的原子分辨率结构。我们提出了一种机制，其中 JC 模板化 IgA 寡聚化并赋予 pIgR 结合和转胞吞作用的不对称性。该框架将为未来基于 IgA 的疗法的设计提供信息。我们确定了通过连接链 (JC) 连接并与 pIgR 的分泌成分复合的二聚体、四聚体和五聚体 IgA-Fc 的原子分辨率结构。我们提出了一种机制，其中 JC 模板化 IgA 寡聚化并赋予 pIgR 结合和转胞吞作用的不对称性。该框架将为未来基于 IgA 的疗法的设计提供信息。