Initially, perforin was considered as the only lytic mediator required for target cell death. Significantly, mice with a defective perforin gene have severely impaired cytolytic activity of CTLs and N'K cells. However, several lines of evidence implicate the serine proteases, granzymes, as an additional component in target cell damage. Purified perforin induces lysis of target cells without DNA fragmentation, whereas the addition of granzyme A or B to intact cells restores the apoptotic activity. Granzyme B cleaves after aspartate, a rare substrate specificity shared only with the cysteine proteinases of the interleukin 1 |3-converting enzyme (ICE) family which are key molecules of apoptosis. Since ICE members require processing at aspartate, it has been speculated that during CTL attack, ICR precursors may be activated by granzyme B and accelerate cell death. Indeed, CTLs from granzyme B knockout mice were found to have impaired apoptotic activity.
See also: Antibody-dependent cellular cytotoxicity; Apoptosis; Cytotoxic T lymphocytes; Cytotoxicity, mechanisms of; Fas (C095) and fas ligand; Granzymes; Natural killer (NK) cells.
Figure 2 Structural organization of human perforin and the terminal complement component C9 and lipid insertion of perforin. Monomeric perforin binds to phosphorylcho-llne (PC) headgroups of lipid membranes. This interaction is strictly Ca2 -dependent and reversible. At physiological temperature, perforin undergoes a drastic conformational change and inserts into the lipid bilayer. Polymerization of the perforin proto-mers ensues. Cylindrical polymers of up to 18 monomers are formed. The largest tubules have an inner diameter of >10 nm. The inset above shows the arrangement of the various structural motifs present in perforin and C9: TS, thrombospondin module; L, LDL receptor class A module; EGF, EGF receptor module; MB, candidate lipld-binding domain.
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