Abstract
The membrane attack complex (MAC) is one of the immune system's first responders. Complement proteins assemble on target membranes to form pores that lyse pathogens and impact tissue homeostasis of self-cells. How MAC disrupts the membrane barrier remains unclear. Here we use electron cryo-microscopy and flicker spectroscopy to show that MAC interacts with lipid bilayers in two distinct ways. Whereas C6 and C7 associate with the outer leaflet and reduce the energy for membrane bending, C8 and C9 traverse the bilayer increasing membrane rigidity. CryoEM reconstructions reveal plasticity of the MAC pore and demonstrate how C5b6 acts as a platform, directing assembly of a giant β-barrel whose structure is supported by a glycan scaffold. Our work provides a structural basis for understanding how β-pore forming proteins breach the membrane and reveals a mechanism for how MAC kills pathogens and regulates cell functions.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Complement C6 / chemistry
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Complement C6 / metabolism
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Complement C6 / ultrastructure
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Complement C7 / chemistry
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Complement C7 / metabolism
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Complement C7 / ultrastructure
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Complement C8 / chemistry
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Complement C8 / metabolism
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Complement C8 / ultrastructure
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Complement C9 / chemistry
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Complement C9 / metabolism
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Complement C9 / ultrastructure
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Complement Membrane Attack Complex / chemistry*
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Complement Membrane Attack Complex / metabolism
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Complement Membrane Attack Complex / ultrastructure*
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Cryoelectron Microscopy / methods*
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Humans
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Image Processing, Computer-Assisted
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Lipid Bilayers / chemistry*
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Lipid Bilayers / metabolism
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Liposomes
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Models, Molecular
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Polysaccharides / metabolism
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Protein Conformation
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Protein Interaction Domains and Motifs
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Spectrum Analysis / methods
Substances
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Complement C6
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Complement C7
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Complement C8
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Complement C9
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Complement Membrane Attack Complex
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Lipid Bilayers
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Liposomes
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Polysaccharides