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Function
Cytolysis/Apoptosis
Perforin is a glycoprotein that is responsible for the pore formation of target cells (T-cells) in the cell membranes. Perforin is stored in the lysosome-like secretory granules of cytotoxic T lymphocytes. This protein is utilized by natural killer (NK) cells and CD8-positive T-cells. Perforin can also be expressed in low amounts in CD4-positive T-cells whenever classic cytotoxicity is disrupted. NK cells and T-cells use perforin molecules to create channels that allow for the transport of ions, water, small-molecule substances, and enzymes. By forming these channels, perforin causes problems with the disruptive barrier of the membranes and thus destroys the solidarity of the T-cells. This is why their function can broadly be identified as apoptosis.
Mechanism
Perforin polymerizes and forms channels in the membrane of the target cells. To do this Calcium ions are required for perforin polymerization and pore formation. These calcium ions are responsible for the transition of inactive perforin to active perforin. To keep things in order, Calreticulin serves as a chaperone protein for this mechanism. It protects perforin by keeping it in the glomerular form which prevents perforin from activation and degradation. The calreticulin binds calcium ions and inhibits spontaneous perforin polymerization inside the granules.
Membrane phospholipids are necessary for perforin to bind target cells. Perforin’s affinity to target cells can be increased by phosphatidylcholine binding with calcium ions. Once perforin is bound to the cell membrane, pores are created which allows for an influx and efflux of ions and polypeptides. This in turn disturbed homeostasis and causes tonic shock. Also, as an indirect effect, this results in the induction of proapoptotic pathways and DNA degradation ultimately leading to cell death.
Relevance
Perforin is a considerable component of research for a wide range of different diseases, infections, autoimmune disorders, and immunopathology.
Structural highlights
Perforin is a 60-70kDa glycoprotein and has a hydrophobic domain. This is why it is able to be incorporated into the lipid membrane of the T-cells. Perforin has 555 amino acids and a mass of 61,377 Da. Each perforin molecule consists of four different domains. Of these domains, two include the N-terminal and C-terminal. The N-terminal domain of perforin contains calcium ions for the binding site that is important for the biological function of perforin. The other two domains are located in the middle of the perforin molecule. The homologous domains contain a sequence that forms two B-sheets and one a-helix structure. It contains a cysteine-rich domain that is homologous to the low-density lipoprotein receptor type B and is also an epithelial growth factor precursor.
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