The Membrane Attack Complex of Complement

Abstract

Cell-killing mechanisms are essential components of host defense against infectious agents, parasites, and malignant cells. We distinguish humoral and cellular killing mechanisms. Complement utilizes specific proteins to assemble its killer molecule. Macrophages generate active oxygen radicals that injure target membranes. Lymphocytes, like complement, use protein molecules as tools in the cellular cytotoxicity reaction. As will be suggested at the conclusion of this chapter, considerable similarity between the structure of the cytolytic apparatus of complement and that of lymphocytes has recently come to light. An in-depth knowledge of the structure and function of the killer molecule of complement may therefore facilitate elucidation of the cell-killing mechanism of lymphocytes. Complement encompasses 20 proteins, not including the various cell­ surface complement receptors and regulatory proteins. Only 5 of these 20 proteins participate directly in cell killing-C5, C6, C7, C8, and C9-and none has enzymatic activity, proteolytic or lipolytic. Upon activation of C5, the 5 proteins interact in a sequential manner and fuse into a macromo­ lecular organization, called the membrarie attack complex or MAC. Fusion brings forth hydrophobic sites through which the complex inserts itself into the hydrocarbon core of lipid membranes. There it forms transmembrane channels, the largest of which constitutes tubular poly C9. Activation of C5 is accomplished by a highly specific serine protease, C5 convertase, itself an assembly of three protein molecules. Thus, formation of the MAC is initiated enzymatically, but this enzyme does not participate in actual membrane attack, which is entirely a physicochemical process.