Department of Anatomy and Structural Biology, Graduate School of Medicine, University of Yamanashi, Chuo, Japan.
Department of Cell Biology and Anatomy, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Elife. 2022 Jun 27;11:e79990. doi: 10.7554/eLife.79990.
Langerhans cells are specialized antigen-presenting cells localized within the epidermis and mucosal epithelium. Upon contact with Langerhans cells, pathogens are captured by the C-type lectin langerin and internalized into a structurally unique vesicle known as a Birbeck granule. Although the immunological role of Langerhans cells and Birbeck granules have been extensively studied, the mechanism by which the characteristic zippered membrane structure of Birbeck granules is formed remains elusive. In this study, we observed isolated Birbeck granules using cryo-electron tomography and reconstructed the 3D structure of the repeating unit of the honeycomb lattice of langerin at 6.4 Å resolution. We found that the interaction between the two langerin trimers was mediated by docking the flexible loop at residues 258-263 into the secondary carbohydrate-binding cleft. Mutations within the loop inhibited Birbeck granule formation and the internalization of HIV pseudovirus. These findings suggest a molecular mechanism for membrane zippering during Birbeck granule biogenesis and provide insight into the role of langerin in the defense against viral infection.
郎格汉斯细胞是定位于表皮和黏膜上皮的一种特化的抗原呈递细胞。在与郎格汉斯细胞接触时，病原体被 C 型凝集素 langerin 捕获，并内化到一种称为 Birbeck 颗粒的结构独特的囊泡中。尽管郎格汉斯细胞和 Birbeck 颗粒的免疫学作用已经得到广泛研究，但 Birbeck 颗粒特征性拉链状膜结构形成的机制仍不清楚。在这项研究中，我们使用冷冻电子断层扫描观察分离的 Birbeck 颗粒，并以 6.4 Å 的分辨率重建郎格汉斯蛋白蜂窝晶格重复单元的 3D 结构。我们发现，两个郎格汉斯三聚体之间的相互作用是通过将残基 258-263 处的柔性环插入到二级碳水化合物结合凹槽来介导的。该环内的突变抑制了 Birbeck 颗粒的形成和 HIV 假病毒的内化。这些发现为 Birbeck 颗粒生物发生过程中的膜拉链形成提供了分子机制，并深入了解了郎格汉斯蛋白在抵御病毒感染中的作用。
