Formation of Membrane Attack Complexes

The formation of a membrane attack complex (MAC) is a downstream event in the complement cascade that occurs after the activation of C3. Here’s a step-by-step overview, starting from the formation of a C3 convertase complex:

1. Formation of C3 Convertase:
   • The complement cascade is triggered by one of the three activation pathways: classical, lectin, or alternative.
   • Activation leads to the formation of a C3 convertase complex, which cleaves the central complement protein C3 into two fragments: C3a and C3b.
2. C3b Binding to Pathogen Surface:
   • C3b, one of the cleavage products of C3, can bind covalently to the surface of pathogens, immune complexes, or host cells that need to be eliminated.
3. Formation of C5 Convertase:
   • The presence of C3b on the pathogen surface allows the assembly of the C5 convertase.
   • For the classical and lectin pathways, C4b2a3b acts as the C5 convertase.
   • For the alternative pathway, C3bBb3b serves as the C5 convertase.
4. Cleavage of C5:
   • The C5 convertase cleaves the complement protein C5 into two fragments: C5a and C5b.
5. Formation of Membrane Attack Complex (MAC):
   • C5b, the larger fragment resulting from the cleavage of C5, forms a complex with C6, C7, C8, and multiple copies of C9 to create the membrane attack complex (MAC).
   • The stepwise assembly is as follows:
     • C5b binds to the target surface.
     • C6 associates with C5b.
     • The C5b-C6 complex binds to C7.
     • C5b-C6-C7 complex binds to C8.
     • The C5b-C6-C7-C8 complex facilitates the polymerization and binding of multiple C9 molecules.
6. Insertion of MAC into Membrane:
   • The polymerized C9 molecules form a pore-like structure that inserts into the lipid bilayer of the target cell membrane.
   • This creates a transmembrane channel called the MAC, or membrane attack complex.
7. Cell Lysis and Death:
   • The formation of the MAC creates pores in the cell membrane of the target pathogen or cell.
   • These pores disrupt the osmotic balance and lead to uncontrolled influx and efflux of ions and molecules.
   • Ultimately, this results in cell lysis and death of the target pathogen or cell.

The membrane attack complex is a potent mechanism employed by the complement system to eliminate pathogens by causing direct damage to their cell membranes.

Control Yourself: Autonomous Complement Pathway Regulation

Source: ChatGPT response prompted and edited by Joel Graff.

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