has enzymatic activity directed against C3. Magnesium ions are necessary for the
formation of the C4b2a complex. C3 is cleaved by the C4b2a complex into two
molecules, C3a and C3b. The smaller C3a (MW 10,000) does not bind to the cell
membrane, but is released into the fluid phase as a mediator of inflammation
(anaphylatoxin I). The C3b molecule (MW 175,000) binds to the cell membrane and
can also bind to its own activation enzyme. As the C4b2a complex is an enzyme, it can
react more than once, and produce a shower of C3b fragments each time. Only the
C3b fragments that become bound adjacent to the C4b2a enzyme, however, are
believed to participate in the next reaction, in which C5 is cleaved.
(3) Membrane attack unit. Some of the C3b molecules combine with C4b2a
to form C4b, 2a, and 3b, which will cleave the C5 molecule into C5a (anaphylatoxin II)
and C5b. This is the last enzymatic reaction in the pathway. C5b appears to bind C6
and C7 by absorption. The resulting trimolecular complex attaches to the cell
membrane and binds C8 and C9. Fully assembled, the membrane attack complex
consists of one molecule of C5b, C6, C7, C8, and up to six molecules of C9. It has a
molecular weight of about one million. The end result of the pathway is lysis of the cell
(see figure 1-4).
d. Electron microscopy shows that lesions start appearing in the cell membrane
after C8 is absorbed, although the cell does not Iyse until C9 is complexed. It is not
understood how these lesions are made. In most instances, the lesions are not large
enough to allow the hemoglobin molecule to escape directly through the lesion, so it is
thought that cell lysis is caused by an osmotic effect. When cells are attacked by
complement, they swell until the cell membrane is ruptured. The cause of the swelling
is salt and water entering the cell. Mayer has postulated a theory he calls his
"doughnut" hypothesis: a stable hole is produced by the assembly of a rigid,
doughnut-shaped structure in the lipid bilayer of the cell membrane. The hole forms a
channel connecting the inside of the cell with the extracellular fluid. The outside of the
doughnut could be composed of nonpolar polypeptides, that is, protein chains that were
hydrophobic; the interior would need polar peptides so that it could be hydrophilic. He
suggests that C5b, C6, C7, C8, and C9 may be the proteins that form the doughnut or
funnel shape, penetrating the lipid bilayer of the membrane.
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