Molecular properties of perforin

The lymphocyte-generated pores are assembled from monomeric perforin (alternative names include pore-forming protein, cytolysin and C9-related protein)

which is stored in electron-dense cytoplasmic granules. These granules also harbor several serine proteases, designated granzymes, and proteoglycans of the chondroitin sulfate A type. Purified perforin has a potent lytic activity and lyses most tumor targets in a nonspecific manner.

Cytoplasmic granules are a common feature of both activated cytotoxic T lymphocytes (CTl.s) and natural killer (NK) cells. Upon T cell receptor-mediated binding of the target cell, granules selectively localize to the contact site, eventually fuse with the plasma membrane and release their contents, including perforin, into the microenvironment between the effector and target cells. It is generally accepted that perforin monomers, upon their release from granules, bind to phosphorylcholine moieties and insert into target cell membranes (Figure 2). This process is strictly Ca2"-dependent. Individual proteins subsequently undergo a conformational change,

Figure 1 Pores formed by perforin (A) and complement C9 (B).

insert into the target membrane, and polymerize in the plane of the membrane, leading to transmembrane channel formation. The internal diameters of perforin pores vary from 5 to 20 nm depending on the number of oligomerized perforins (2-18).

The mature perforin exhibits a molecular weight of 65-75 kDa and has a pi of 6.44. The mouse, rat and human cDNAs coding for perforin have been sequenced, predicting a protein of 534 amino acids (mouse). The central portion of perforin, containing the membrane interaction site, shows sequence homology with C9. This central segment is likely to be responsible for the structural and functional similarities between the two proteins, in particular the capacity to polymerize into similar tubules and to insert into the membrane. The C-terminal portion of perforin includes a C2 domain initially characterized in protein kinase C. C2 domains arc thought to be involved in calcium-dependent phospholipid binding.

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