Complement Attack Mechanism

The C attack proteins are subject to control by three mechanisms that also limit the activity of the early-acting components decay of labile binding sites, breakdown of active components to inactive products by enzymes, and inhibition by control proteins which do not act enzymatically. 

As mentioned earlier, C5b has only transient hemolytic activity, and unless it is stabilized by C6 it rapidly decays, both in the fluid phase and on the target cell surface (Cooper and Miiller-Eberhard, 1970 Shin et al., 91 a,b). The evanescence of the membrane-binding site on the C567 complex has been commented on by several investigators (Lachmann and Thompson, 1970 Gotze and Miiller-Eberhard, 1970 Goldman et al., 1972). 

Several inhibitors of the individual attack components have been described, but none is well characterized. A C6 inactivator which blocks cell-bound but not fluid-phase C6 has been reported but only partially characterized (Tamuraand Nelson, 1%7 Nelson and Biro, 1%8 Goldlust et al., 1974). A C7 inhibitor has been found in two patients with C7 deficiency (Wellek and Opferkuch, 1975 Lint et al., W66), but a definitive characterization is still lacking. A C56 inhibitor has also been described, but its chziracterization remains to be completed (Lint et al., 1975). A molecule derived from inactive C8 has been reported to act as a specific C8 inhibitor (Stolfi, 1968), but its occurrence in vivo is ques-tionable. Also, hemolytically inactive complexes of C567, C5678, and 

C5b-9 have been shown to inhibit the classical C pathway, probably by competing with their active counterparts for native C8 and C9 (Koethe et aL, 1973 Kolb and Muller-Eberhard, 1973). 

This review was completed prior to the Seventh International Complement Workshop. We have made a few additions after the Workshop and updated the text. Notably the agreement by several groups that C3Nef is an immunoglobulin capable of reacting with the C3bBb conver- 

---

The last five components (C5-C9) of the complement system compose what has been called the membrane attack mechanism (Miiller-Eberhard, 1972), for it is the action of these proteins, functioning as a unit, which causes a lesion in the target membrane capable of producing lysis. This is shown schematically in Fig. 7. The attack mechanism was also recently reviewed in detail by M. Mayer in a Harvey Lecture (1977). 

Since the C attack mechanism seems to assemble spontaneously on cleavage of native C5, any enzyme which can produce C5b may activate the sequence. However, the most thoroughly studied activators are the complex enzymes of the complement system for which C5 can be considered the natural substrate. ... 

It makes good sense to draw free-radical mechanisms in the manner shown by these examples. However, shorter versions may be encountered in which not all of the arrows are actually drawn. These versions bear considerable similarity to two-electron curly arrow mechanisms, in that a fishhook arrow is shown attacking an atom, and a second fishhook arrow is then shown leaving this atom. The other electron movement is not shown, but is implicit. This type of representation is quite clear if the complement of electrons around a particular atom is counted each time but, if in any doubt, use all the necessary fishhook arrows. 

MHz of the histidine residues of the human C isozyme has been completed/ which complements the earlier study on the B isozyme the results of pH titrations and anion additions were consistent with an activity linked ionizable zinc-bound water molecule. The residue Thr-199 may also have a role in the catalytic mechanism, facilitating the polarization of COj and attack by the hydroxide, as shown in Scheme 2. 

---