Insights into IgM-mediated complement activation based on in situ structures of IgM-C1-C4b

Researchers in the Sharp lab solved the structures of IgM antibodies with multiple components of the immune complement system, revealing insights into immune system activation.

IgM antibodies protect us against infections and mediate clearance of cellular debris by activating the immune complement system upon binding to cell-surface antigens. Using 3D cryo-electron tomography, Sharp et al. were able to image activation of the immune system complement cascade by IgM antibodies. Hexameric and pentameric IgM antibodies (green) bind to surface-antigens and undergo a structural rearrangement that exposes binding sites for the hexameric C1q protein complex (blue). Binding of C1q induces activation of proteins C1r (purple) and C1s (pink). C1s then enzymatically cleaves C4 to form C4b (cyan) and initiate the complement cascade. The results indicate a surface trigger that activates complement and contributes to differentiating between silent removal of targeted host cells versus raising inflammatory responses to invading microbes.


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