Cryo-electron tomography of Birbeck granules reveals the molecular mechanism of langerin lattice formation

Abstract

Langerhans cells are specialized antigen-presenting cells localized within the epidermis and mucosal tissue. 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 258-262 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.

Langerin-expressing dendritic cells in pulmonary immune-related diseases

“…Langerin-deficient mice lack BG and the introduction of the langerin gene into embryonic fibroblasts induces the formation of BG ( 20 ). Oda et al rebuilt the 3D structure of isolated BGs using cryo-electron tomography and identified a flexible loop region within langerin trimers that is crucial for BG formation and viral internalization ( 30 ).…”