The first step in the formation of the membrane-attack complex is the cleavage of C5 by a C5 convertase to release C5b (see Fig. 2.29). In the next stages (see Fig. 2.35), C5b initiates the assembly of the later complement components and their insertion into the cell membrane. The process begins when one molecule of C5b binds one molecule of C6, and the C5b6 complex then binds one molecule of C7. This reaction leads to a conformational change in the constituent molecules, with the exposure of a hydrophobic site on C7, which inserts into the lipid bilayer. Similar hydrophobic sites are exposed on the later components C8 and C9 when they are bound to the complex, allowing these proteins also to insert into the lipid bilayer. C8 is a complex of two proteins, C8β and C8α-γ. The C8β protein binds to C5b, and the binding of C8β to the membrane-associated C5b67 complex allows the hydrophobic domain of C8α-γ to insert into the lipid bilayer. Finally, C8α-γ induces the polymerization of 10–16 molecules of C9 into a pore-forming structure called the membrane-attack complex. The membrane-attack complex has a hydrophobic external face, allowing it to associate with the lipid bilayer, but a hydrophilic internal channel. The diameter of this channel is about 10 nm, allowing the free passage of solutes and water across the lipid bilayer. The pore damage to the lipid bilayer leads to the loss of cellular homeostasis, the disruption of the proton gradient across the membrane, the penetration of enzymes such as lysozyme into the cell, and the eventual destruction of the pathogen.
Although the effect of the membrane-attack complex is very dramatic, particularly in experimental demonstrations in which antibodies against red blood cell membranes are used to trigger the complement cascade, the significance
The complement system and innate immunity.
Fig. 2.35 Assembly of the membrane-attack complex polymerization of C9, again with the exposure of a hydrophobic generates a pore in the lipid bilayer membrane. The sequence site. Up to 16 molecules of C9 are then added to the assembly of steps and their approximate appearance are shown here in to generate a channel 10 nm in diameter in the membrane. This schematic form. C5b triggers the assembly of a complex of channel disrupts the bacterial cell membrane, killing the bacterium. one molecule each of C6, C7, and C8, in that order. C7 and C8 The electron micrographs show erythrocyte membranes with undergo conformational changes, exposing hydrophobic domains membrane-attack complexes in two orientations, end on and side that insert into the membrane. This complex causes moderate on. Photographs courtesy of S. Bhakdi and J. Tranum-Jensen. membrane damage in its own right, and also serves to induce the of these components in host defense seems to be quite limited. So far, deficiencies in complement components C5–C9 have been associated with susceptibility only to Neisseria species, the bacteria that cause the sexually transmitted disease gonorrhea and a common form of bacterial meningitis. Thus, the opsonizing and inflammatory actions of the earlier components of the complement cascade are clearly more important for host defense against infection. Formation of the membrane-attack complex seems to be important only for the killing of a few pathogens, although, as we will see in Chapter 15, this complex might well have a major role in immunopathology.
of complement activation and protect the host from their destructive effects.