补体膜攻击复合物
表位
补体系统
四级结构
细胞生物学
抗体
生物
细菌外膜
蛋白质结构
化学
生物化学
免疫学
大肠杆菌
蛋白质亚单位
基因
作者
Charles Bayly-Jones,Bill Hy Tran Ho,Corinna Lau,Eleanor W. W. Leung,Laura D’Andrea,Christopher J. Lupton,Susan M. Ekkel,Hariprasad Venugopal,James C. Whisstock,Tom Eirik Mollnes,Bradley A. Spicer,Michelle A. Dunstone
标识
DOI:10.1038/s42003-023-04431-y
摘要
The Membrane Attack Complex (MAC) is responsible for forming large β-barrel channels in the membranes of pathogens, such as gram-negative bacteria. Off-target MAC assembly on endogenous tissue is associated with inflammatory diseases and cancer. Accordingly, a human C5b-9 specific antibody, aE11, has been developed that detects a neoepitope exposed in C9 when it is incorporated into the C5b-9 complex, but not present in the plasma native C9. For nearly four decades aE11 has been routinely used to study complement, MAC-related inflammation, and pathophysiology. However, the identity of C9 neoepitope remains unknown. Here, we determined the cryo-EM structure of aE11 in complex with polyC9 at 3.2 Å resolution. The aE11 binding site is formed by two separate surfaces of the oligomeric C9 periphery and is therefore a discontinuous quaternary epitope. These surfaces are contributed by portions of the adjacent TSP1, LDLRA, and MACPF domains of two neighbouring C9 protomers. By substituting key antibody interacting residues to the murine orthologue, we validated the unusual binding modality of aE11. Furthermore, aE11 can recognise a partial epitope in purified monomeric C9 in vitro, albeit weakly. Taken together, our results reveal the structural basis for MAC recognition by aE11.
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