A key complex in B cell activation A core component of the immune system are B cells, which are activated by infection and then mature to provide long-lived immunity. Activation is initiated when a cell surface B cell receptor, in association with its coreceptor, recognizes an antigen. Susa et al. report a structure of the B cell receptor CD81 in complex with its co receptor, CD19. CD81 alone binds to cholesterol, but the conformational changes associated with binding to CD19 occlude the cholesterol-binding pocket. Regulating cholesterol binding could play a role in the activation mechanism. The structure also provides a basis for the design of immunotherapies. Science, this issue p. 300 The structure of the immunological B cell co-receptor complex reveals a substantial conformational reorganization of the tetraspanin CD81. Signaling through the CD19-CD81 co-receptor complex, in combination with the B cell receptor, is a critical determinant of B cell development and activation. It is unknown how CD81 engages CD19 to enable co-receptor function. Here, we report a 3.8-angstrom structure of the CD19-CD81 complex bound to a therapeutic antigen-binding fragment, determined by cryo–electron microscopy (cryo-EM). The structure includes both the extracellular domains and the transmembrane helices of the complex, revealing a contact interface between the ectodomains that drives complex formation. Upon binding to CD19, CD81 opens its ectodomain to expose a hydrophobic CD19-binding surface and reorganizes its transmembrane helices to occlude a cholesterol binding pocket present in the apoprotein. Our data reveal the structural basis for CD19-CD81 complex assembly, providing a foundation for rational design of therapies for B cell dysfunction.

中文翻译：

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B 细胞共受体 CD19 与四跨膜蛋白 CD81 结合的冷冻电镜结构

B 细胞激活的关键复合物 免疫系统的核心组成部分是 B 细胞，它们在感染后被激活，然后成熟以提供长期免疫。当细胞表面 B 细胞受体与其辅助受体结合识别抗原时，激活就开始了。苏萨等人。报告了 B 细胞受体 CD81 与其辅受体 CD19 复合物的结构。CD81 单独与胆固醇结合，但与 CD19 结合相关的构象变化阻塞了胆固醇结合口袋。调节胆固醇结合可能在激活机制中发挥作用。该结构还为免疫疗法的设计提供了基础。科学，这个问题 p。300 免疫学 B 细胞共受体复合物的结构揭示了四跨膜蛋白 CD81 的实质性构象重组。通过 CD19-CD81 共受体复合物与 B 细胞受体结合的信号传导是 B 细胞发育和激活的关键决定因素。尚不清楚 CD81 如何与 CD19 结合以启用共同受体功能。在这里，我们报告了与治疗性抗原结合片段结合的 CD19-CD81 复合物的 3.8 埃结构，通过冷冻电子显微镜（cryo-EM）确定。该结构包括复合物的胞外域和跨膜螺旋，揭示了驱动复合物形成的胞外域之间的接触界面。与 CD19 结合后，CD81 打开其胞外域以暴露疏水性 CD19 结合表面并重组其跨膜螺旋以封闭载脂蛋白中存在的胆固醇结合口袋。我们的数据揭示了 CD19-CD81 复合体组装的结构基础，