Perforin

Perforin-1 is a protein that in humans is encoded by the PRF1 gene and the Prf1 gene in mice.[5][6][7]

Not to be confused with Porphyrin.

PRF1
Identifiers
Aliases	PRF1, FLH2, HPLH2, P1, PFN1, PFP, perforin 1
External IDs	OMIM: 170280 MGI: 97551 HomoloGene: 3698 GeneCards: PRF1
Gene location (Human) Chr. Chromosome 10 (human)[1] Band 10q22.1 Start 70,597,348 bp[1] End 70,602,759 bp[1]
Gene location (Mouse) Chr. Chromosome 10 (mouse)[2] Band 10 B4|10 32.18 cM Start 61,297,833 bp[2] End 61,304,680 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • GO:0001948 protein binding • metal ion binding • calcium ion binding • wide pore channel activity • identical protein binding Cellular component • integral component of membrane • extracellular region • endosome • cell membrane • endosome lumen • membrane • cytosol • cytoplasmic vesicle • cytolytic granule Biological process • cellular defense response • immunological synapse formation • cytolysis • apoptotic process • transmembrane transport • positive regulation of killing of cells of other organism • defense response to tumor cell • immune response to tumor cell • protein homooligomerization • defense response to virus • T cell mediated cytotoxicity Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	5551	18646
Ensembl	ENSG00000180644	ENSMUSG00000037202
UniProt	P14222	P10820
RefSeq (mRNA)	NM_005041 NM_001083116	NM_011073
RefSeq (protein)	NP_001076585 NP_005032	NP_035203
Location (UCSC)	Chr 10: 70.6 – 70.6 Mb	Chr 10: 61.3 – 61.3 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

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.[8] The lytic membrane-inserting part of perforin is the MACPF domain.[9] This region shares homology with cholesterol-dependent cytolysins from Gram-positive bacteria.[10]

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.[7] 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.[11]

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.[7]

Interactions

Perforin has been shown to interact with calreticulin.[12]

See also

• Granzymes
• Defensin
• Complement membrane attack complex

References

1. GRCh38: Ensembl release 89: ENSG00000180644 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000037202 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. 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. PMID 1505959.
6. 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. PMID 2592021.
7. "Entrez Gene: PRF1 perforin 1 (pore forming protein)".
8. 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. PMID 8770355.
9. 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. Bibcode:1986Natur.322..831T. doi:10.1038/322831a0. PMID 2427956.
10. 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. Bibcode:2007Sci...317.1548R. doi:10.1126/science.1144706. PMID 17717151.
11. Thiery J, Keefe D, Boulant S, Boucrot E, Walch M, Martinvalet D, Goping IS, Bleackley RC, Kirchhausen T, Lieberman J (2011). "Perforin pores in the endosomal membrane trigger the release of endocytosed granzyme B into the cytosol of target cells". Nat. Immunol. 12 (8): 770–7. doi:10.1038/ni.2050. PMC 3140544. PMID 21685908.
12. 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. PMID 9671507.

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. PMID 8770355.
• 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. PMID 2395434.
• 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. PMID 2420467.
• 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. PMID 2425429.
• 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. PMID 2480391.
• Shinkai Y, Takio K, Okumura K (1988). "Homology of perforin to the ninth component of complement (C9)". Nature. 334 (6182): 525–7. Bibcode:1988Natur.334..525S. doi:10.1038/334525a0. PMID 3261391.
• Lichtenheld MG, Olsen KJ, Lu P, et al. (1988). "Structure and function of human perforin". Nature. 335 (6189): 448–51. Bibcode:1988Natur.335..448L. doi:10.1038/335448a0. PMID 3419519.
• 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. PMID 8676885.
• Nöske K, Bilzer T, Planz O, Stitz L (1998). "Virus-Specific CD4+ T Cells Eliminate Borna Disease Virus from the Brain via Induction of Cytotoxic CD8+ T Cells". J. Virol. 72 (5): 4387–95. PMC 109669. PMID 9557729.
• 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. PMID 9671507.
• 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. PMID 10072525.
• 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. PMID 10583959.
• 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. PMID 10779745.
• 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. PMID 11082062.
• Göransdotter Ericson K, Fadeel B, Nilsson-Ardnor S, et al. (2001). "Spectrum of Perforin Gene Mutations in Familial Hemophagocytic Lymphohistiocytosis". Am. J. Hum. Genet. 68 (3): 590–7. doi:10.1086/318796. PMC 1274472. PMID 11179007.
• Clementi R, zur Stadt U, Savoldi G, et al. (2002). "Six novel mutations in the PRF1 gene in children with haemophagocytic lymphohistiocytosis". J. Med. Genet. 38 (9): 643–6. doi:10.1136/jmg.38.9.643. PMC 1734943. PMID 11565555.
• 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. PMID 11586066.

External links

• perforin at the US National Library of Medicine Medical Subject Headings (MeSH)

Perforin at NLM Genetics Home Reference