Membrane attack complex

The membrane attack complex is an immunological defense system coordinated and integrated by the individual components of the complement system with the goal of eliminating an endogenous or exogenously invaded pathogenic cell by cytolysis. The generation of the membrane attack complex is an essential part of innate (non-specific) immunity.

The formation of the membrane attack complex is initiated by the activation of the complement system. 3 activation pathways of the complement system are known:

• Classical activation pathway by antigen-antibody complexes (IgM-, IgG1-, IgG2-, IgG3-containing immune complexes).
• Lectin activation pathway through carbohydrates of the bacterial cell wall (acetylglycosamines, mannose).
• Alternative activation pathway by direct attachment of complement protein C3 to pathogens whose membrane is poor in syalinic acid, endotoxins ( LPS), viruses, fungi, parasites, IgG-, IgA- and IgE-containing immune complexes.

The activation cascade is initiated via C1q. C1q is composed of 6 subunits with globular heads and collagen-like tails. C1q binds directly to pathogen surface or indirectly to pathogen-bound antibody, enabling the autoactivation of C1r and C1s (Fig.). Activated C1s cleaves C4 and C2. C4b2a is an active C3 convertase that cleaves C3 into C3a and C3b. C3b binds to C4b2a to form the active C5 convertase that cleaves C5 into C5a and C5b. C5b binds to the cell surface and leads to the formation of the terminal complement components in this pathway.

The complement components C6 and C7 group around C5 to form a C5b67 complex. Thereafter, component C8 still attaches to form a larger C5b678 complex (p. Fig.). C8 itself is a complex of the two subunits C8-β and C8-α-γ. The C8-α-γ subunit is hydrophobic and penetrates the bilayer of the cell membrane. It initiates the polymerization of the complement component C9. 10-16 C9 molecules together form a ring-shaped transmembrane structure. Here, the hydrophobic side of the C9 polymers faces the cell membrane, while the hydrophilic side faces the center of the pore.

This arrangement leads to the tubular structure of the membrane attack complex in the target cell (see Fig.). This transmembrane tube (pore) has a diameter of about 10 nm. These perforations, caused by complement fractions, disrupt the selective permeability of the cell membrane. Penetrating water leads to loss of cell integrity and finally to osmotic lysis of the cell.

1. Doorduijn DJ et al (2019) How the Membrane Attack Complex Damages the Bacterial Cell Envelope and Kills Gram-Negative Bacteria. Bioessays 41:e1900074.
2. Moreno hail screen G et al. (2017) The Membrane Attack Complex/Perforin Superfamily. J Mol Microbiol Biotechnol 27:252-267.
3. Morgan BP et al. (2017). Molecular cell biology of complement membrane attack. Seminars in cell & developmental biology 72: 124-132.