The bactericidal mechanism of the complement membrane attack complex
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The complement system is an important innate immune defense, containing about 30 secreted and membrane-bound factors. To fight bacterial infections, these factors collaborate to opsonize bacteria, attract phagocytic cells and to lyse Gram-negative bacteria via membrane-insertion of the membrane attack complex (MAC). The bactericidal MAC is generated via a specific assembly sequence initiated by the labile C5b, and followed by C6 and C7 to form the membrane-associated C5b-7 complex. The assembly is complete after incorporation of C8 and multiple C9 molecules, the complement factors that traverse the membrane. Although the assembly has been studied in detail, it is still controversial how insertion of the MAC leads to bacterial killing. Especially, since fully assembled MACs can been found in the envelope of Gram-positive and complement-resistant Gram-negative bacteria. Unraveling the bactericidal mechanism of the MAC might provide new insights into the MAC-resistant phenotypes, and can be a target for new therapeutic interventions. This review describes the assembly of the MAC in detail, including recently determined 3D structures of the complement proteins. This data emphasizes the time- and sequence-specific assembly of the MAC. Second, the characteristics of the membrane lesions in model systems, e.g. erythrocytes and artificial lipid bilayers, are discussed. Finally, models of the bactericidal mechanism of the MAC are reviewed and new directions in MAC research are proposed.