Perforin is a pore forming cytolytic protein found in the granules of cytotoxic T lymphocytes (CTLs) and Natural Killer cells (NK cells). Upon degranulation, perforin binds to the target cell's plasma membrane, and oligomerises in a Ca2+ dependent manner to form pores on the target cell. The pore formed allows for the passive diffusion of a family of pro-apoptotic proteases, known as the granzymes, into the target cell.[4] The lytic membrane-inserting part of perforin is the MACPF domain.[5] This region shares homology with cholesterol-dependent cytolysins from Gram-positive bacteria.[6]
Perforin has structural and functional similarities to complement component 9 (C9). Like C9, this protein creates transmembrane tubules and is capable of lysing non-specifically a variety of target cells. This protein is one of the main cytolytic proteins of cytolytic granules, and it is known to be a key effector molecule for T-cell- and natural killer-cell-mediated cytolysis.[3] Perforin is thought to act by creating holes in the plasma membrane which triggers an influx of calcium and initiates membrane repair mechanisms. These repair mechanisms bring perforin and granzymes into early endosomes.[7]
Clinical significance
Homozygous inheritance of defective PRF1 alleles result in the development of familial hemophagocytic lymphohistiocytosis type 2 (FHL2), a rare and lethal autosomal recessive disorder of infancy.[3]
↑Fink TM, Zimmer M, Weitz S, Tschopp J, Jenne DE, Lichter P (Sep 1992). "Human perforin (PRF1) maps to 10q22, a region that is syntenic with mouse chromosome 10". Genomics. 13 (4): 1300–2. doi:10.1016/0888-7543(92)90050-3. PMID1505959.
↑Shinkai Y, Yoshida MC, Maeda K, Kobata T, Maruyama K, Yodoi J, Yagita H, Okumura K (Jan 1990). "Molecular cloning and chromosomal assignment of a human perforin (PFP) gene". Immunogenetics. 30 (6): 452–7. doi:10.1007/BF02421177. PMID2592021.
↑Trapani JA (1996). "Target cell apoptosis induced by cytotoxic T cells and natural killer cells involves synergy between the pore-forming protein, perforin, and the serine protease, granzyme B". Australian and New Zealand journal of medicine. 25 (6): 793–9. doi:10.1111/j.1445-5994.1995.tb02883.x. PMID8770355.
↑Tschopp J, Masson D, Stanley KK (1986). "Structural/functional similarity between proteins involved in complement- and cytotoxic T-lymphocyte-mediated cytolysis". Nature. 322 (6082): 831–4. doi:10.1038/322831a0. PMID2427956.
↑Rosado CJ, Buckle AM, Law RH, Butcher RE, Kan WT, Bird CH, Ung K, Browne KA, Baran K, Bashtannyk-Puhalovich TA, Faux NG, Wong W, Porter CJ, Pike RN, Ellisdon AM, Pearce MC, Bottomley SP, Emsley J, Smith AI, Rossjohn J, Hartland EL, Voskoboinik I, Trapani JA, Bird PI, Dunstone MA, Whisstock JC (2007). "A common fold mediates vertebrate defense and bacterial attack". Science. 317 (5844): 1548–51. doi:10.1126/science.1144706. PMID17717151.
↑Andrin C, Pinkoski MJ, Burns K, et al. (July 1998). "Interaction between a Ca2+-binding protein calreticulin and perforin, a component of the cytotoxic T-cell granules". Biochemistry. 37 (29): 10386–94. doi:10.1021/bi980595z. PMID9671507.
Further reading
Trapani JA (1996). "Target cell apoptosis induced by cytotoxic T cells and natural killer cells involves synergy between the pore-forming protein, perforin, and the serine protease, granzyme B". Australian and New Zealand journal of medicine. 25 (6): 793–9. doi:10.1111/j.1445-5994.1995.tb02883.x. PMID8770355.
Peitsch MC, Amiguet P, Guy R, et al. (1990). "Localization and molecular modelling of the membrane-inserted domain of the ninth component of human complement and perforin". Mol. Immunol. 27 (7): 589–602. doi:10.1016/0161-5890(90)90001-G. PMID2395434.
Young JD, Hengartner H, Podack ER, Cohn ZA (1986). "Purification and characterization of a cytolytic pore-forming protein from granules of cloned lymphocytes with natural killer activity". Cell. 44 (6): 849–59. doi:10.1016/0092-8674(86)90007-3. PMID2420467.
Young JD, Cohn ZA, Podack ER (1986). "The ninth component of complement and the pore-forming protein (perforin 1) from cytotoxic T cells: structural, immunological, and functional similarities". Science. 233 (4760): 184–90. doi:10.1126/science.2425429. PMID2425429.
Lichtenheld MG, Podack ER (1990). "Structure of the human perforin gene. A simple gene organization with interesting potential regulatory sequences". J. Immunol. 143 (12): 4267–74. PMID2480391.
Shinkai Y, Takio K, Okumura K (1988). "Homology of perforin to the ninth component of complement (C9)". Nature. 334 (6182): 525–7. doi:10.1038/334525a0. PMID3261391.
Lichtenheld MG, Olsen KJ, Lu P, et al. (1988). "Structure and function of human perforin". Nature. 335 (6189): 448–51. doi:10.1038/335448a0. PMID3419519.
Goebel WS, Schloemer RH, Brahmi Z (1996). "Target cell-induced perforin mRNA turnover in NK3.3 cells is mediated by multiple elements within the mRNA coding region". Mol. Immunol. 33 (4–5): 341–9. doi:10.1016/0161-5890(95)00155-7. PMID8676885.
Andrin C, Pinkoski MJ, Burns K, et al. (1998). "Interaction between a Ca2+-binding protein calreticulin and perforin, a component of the cytotoxic T-cell granules". Biochemistry. 37 (29): 10386–94. doi:10.1021/bi980595z. PMID9671507.
Yu CR, Ortaldo JR, Curiel RE, et al. (1999). "Role of a STAT binding site in the regulation of the human perforin promoter". J. Immunol. 162 (5): 2785–90. PMID10072525.
Stepp SE, Dufourcq-Lagelouse R, Le Deist F, et al. (1999). "Perforin gene defects in familial hemophagocytic lymphohistiocytosis". Science. 286 (5446): 1957–9. doi:10.1126/science.286.5446.1957. PMID10583959.
Takahashi T, Nieda M, Koezuka Y, et al. (2000). "Analysis of human V alpha 24+ CD4+ NKT cells activated by alpha-glycosylceramide-pulsed monocyte-derived dendritic cells". J. Immunol. 164 (9): 4458–64. doi:10.4049/jimmunol.164.9.4458. PMID10779745.
Badovinac VP, Tvinnereim AR, Harty JT (2000). "Regulation of antigen-specific CD8+ T cell homeostasis by perforin and interferon-gamma". Science. 290 (5495): 1354–8. doi:10.1126/science.290.5495.1354. PMID11082062.
Ambach A, Bonnekoh B, Gollnick H (2001). "Perforin granule release from cytotoxic lymphocytes ex vivo is inhibited by ciclosporin but not by methotrexate". Skin Pharmacol. Appl. Skin Physiol. 14 (5): 249–60. doi:10.1159/000056355. PMID11586066.