Skip to main content

Part of the book series: Springer Series in Biophysics ((BIOPHYSICS,volume 18))

Abstract

“Perforins” – cytotoxic cell perforin-1, proteins contributing to the complement membrane attack complex (MAC) and other perforin-like proteins – form unconventional pores in biological membranes in the sense that as well as a ring of subunits circumscribing an opening in the lipid bilayer, arcs of subunits induce similar effects. The resulting arc-pore structures are completed by a lipidic edge, conferring distinctive functional characteristics on them. Electrophysiological measurements have played a distinguished role in the discovery and characterisation of this alternative mechanism of pore formation which enables the same protein to form widely-varying sizes of pore and enact a greater diversity of effects than more conventional channels. This review discusses the mechanism of pore formation by the perforins and the way in which it has been illuminated by electrical conductance studies alongside imaging methods such as electron microscopy and atomic force microscopy.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Aleshin AE, Schraufstatter IU, Stec B, Bankston LA, Liddington RC, Discipio RG (2012) Structure of complement C6 suggests a mechanism for initiation and unidirectional, sequential assembly of the Membrane Attack Complex (MAC). J Biol Chem 287:10210–10222

    CAS  PubMed  PubMed Central  Google Scholar 

  • Amiguet P, Brunner J, Tschopp J (1985) The membrane attack complex of complement: lipid insertion of tubular and nontubular polymerized C9. Biochemistry 24(25):7328–7334

    CAS  PubMed  Google Scholar 

  • Amino R, Giovannini D, Thiberge S, Gueirard P, Boisson B, Dubremetz JF, Prevost MC, Ishino T, Yuda M, Menard R (2008) Host cell traversal is important for progression of the malaria parasite through the dermis to the liver. Cell Host Microbe 3(2):88–96

    CAS  PubMed  Google Scholar 

  • Anderluh G, Gilbert RJC (2014) MACPF/CDC proteins – agents of defence, attack and invasion. In: Subcellular biochemistry, vol 80. Springer, Dordrecht

    Google Scholar 

  • Anderluh G, Dalla Serra M, Viero G, Guella G, Macek P, Menestrina G (2003) Pore formation by equinatoxin II, a eukaryotic protein toxin, occurs by induction of nonlamellar lipid structures. J Biol Chem 278(46):45216–45223. doi:10.1074/jbc.M305916200

    Article  CAS  PubMed  Google Scholar 

  • Benz R, Schmid A, Wiedmer T, Sims PJ (1986) Single-channel analysis of the conductance fluctuations induced in lipid bilayer membranes by complement proteins C5b-9. J Membr Biol 94(1):37–45

    CAS  PubMed  Google Scholar 

  • Bergstrom CL, Beales PA, Lv Y, Vanderlick TK, Groves JT (2013) Cytochrome c causes pore formation in cardiolipin-containing membranes. Proc Natl Acad Sci U S A 110(16):6269–6274. doi:10.1073/pnas.1303819110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bhakdi S, Tranum-Jensen J (1991) Complement lysis: a hole is a hole. Immunol Today 12(9):318–320; discussion 321. doi: 10.1016/0167-5699(91)90007-G

    CAS  PubMed  Google Scholar 

  • Bhakdi S, Tranum-Jensen J, Sziegoleit A (1985) Mechanism of membrane damage by streptolysin-O. Infect Immun 47(1):52–60

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bleicken S, Jeschke G, Stegmueller C, Salvador-Gallego R, Garcia-Saez AJ, Bordignon E (2014) Structural model of active Bax at the membrane. Mol Cell 56(4):496–505. doi:10.1016/j.molcel.2014.09.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Borsos T, Dourmashkin RR, Humphrey JH (1964) Lesions in erythrocyte membranes caused by immune haemolysis. Nature 202:251–252

    CAS  PubMed  Google Scholar 

  • D’Angelo ME, Dunstone MA, Whisstock JC, Trapani JA, Bird PI (2012) Perforin evolved from a gene duplication of MPEG1, followed by a complex pattern of gene gain and loss within Euteleostomi. BMC Evol Biol 12:59. doi:10.1186/1471-2148-12-59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Davis SJ, van der Merwe PA (2011) Lck and the nature of the T cell receptor trigger. Trends Immunol 32(1):1–5. doi:10.1016/j.it.2010.11.003

    Article  CAS  PubMed  Google Scholar 

  • Dunstone MA, Tweten RK (2012) Packing a punch: the mechanism of pore formation by cholesterol dependent cytolysins and membrane attack complex/perforin-like proteins. Curr Opin Struct Biol 22(3):342–349. doi:10.1016/j.sbi.2012.04.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dustin ML, Depoil D (2011) New insights into the T cell synapse from single molecule techniques. Nat Rev Immunol 11(10):672–684. doi:10.1038/nri3066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Felzen B, Berke G, Rosen D, Binah O (1994a) Mechanisms whereby cytotoxic T lymphocytes damage guinea-pig ventricular myocytes in vitro. Pflugers Arch 427(5–6):422–431

    CAS  PubMed  Google Scholar 

  • Felzen B, Berke G, Rosen D, Coleman R, Tschopp J, Young JD, Binah O (1994b) Effects of purified perforin and granzyme A from cytotoxic T lymphocytes on guinea pig ventricular myocytes. Cardiovasc Res 28(5):643–649

    CAS  PubMed  Google Scholar 

  • Fields KA, McCormack R, de Armas LR, Podack ER (2013) Perforin-2 restricts growth of Chlamydia trachomatis in macrophages. Infect Immun 81(8):3045–3054. doi:10.1128/IAI.00497-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Froelich CJ, Pardo J, Simon MM (2009) Granule-associated serine proteases: granzymes might not just be killer proteases. Trends Immunol 30(3):117–123. doi:10.1016/j.it.2009.01.002

    Article  CAS  PubMed  Google Scholar 

  • Fuertes G, Garcia-Saez AJ, Esteban-Martin S, Gimenez D, Sanchez-Munoz OL, Schwille P, Salgado J (2010) Pores formed by Baxalpha5 relax to a smaller size and keep at equilibrium. Biophys J 99(9):2917–2925. doi:10.1016/j.bpj.2010.08.068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fuertes G, Gimenez D, Esteban-Martin S, Sanchez-Munoz OL, Salgado J (2011) A lipocentric view of peptide-induced pores. Eur Biophys J 40(4):399–415. doi:10.1007/s00249-011-0693-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garcia-Saez AJ, Mingarro I, Perez-Paya E, Salgado J (2004) Membrane-insertion fragments of Bcl-xL, Bax, and Bid. Biochemistry 43(34):10930–10943. doi:10.1021/bi036044c

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Saez AJ, Chiantia S, Salgado J, Schwille P (2007) Pore formation by a Bax-derived peptide: effect on the line tension of the membrane probed by AFM. Biophys J 93(1):103–112. doi:10.1529/biophysj.106.100370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garg S, Agarwal S, Kumar S, Yazdani SS, Chitnis CE, Singh S (2013) Calcium-dependent permeabilization of erythrocytes by a perforin-like protein during egress of malaria parasites. Nat Commun 4:1736. doi:10.1038/ncomms2725

    Article  CAS  PubMed  Google Scholar 

  • Gilbert RJ (2002) Pore-forming toxins. Cell Mol Life Sci 59(5):832–844

    CAS  PubMed  Google Scholar 

  • Gilbert RJ (2005) Inactivation and activity of cholesterol-dependent cytolysins: what structural studies tell us. Structure 13(8):1097–1106

    CAS  PubMed  Google Scholar 

  • Gilbert RJ (2010) Cholesterol-dependent cytolysins. Adv Exp Med Biol 677:56–66

    CAS  PubMed  Google Scholar 

  • Gilbert RJ, Jimenez JL, Chen S, Tickle IJ, Rossjohn J, Parker M, Andrew PW, Saibil HR (1999) Two structural transitions in membrane pore formation by pneumolysin, the pore-forming toxin of Streptococcus pneumoniae. Cell 97(5):647–655

    CAS  PubMed  Google Scholar 

  • Gilbert RJ, Mikelj M, Dalla Serra M, Froelich CJ, Anderluh G (2013) Effects of MACPF/CDC proteins on lipid membranes. Cell Mol Life Sci 70(12):2083–2098. doi:10.1007/s00018-012-1153-8

    Article  CAS  PubMed  Google Scholar 

  • Gilbert RJ, Dalla Serra M, Froelich CJ, Wallace MI, Anderluh G (2014) Membrane pore formation at protein-lipid interfaces. Trends Biochem Sci 39:510–516

    CAS  PubMed  Google Scholar 

  • Hadders MA, Beringer DX, Gros P (2007) Structure of C8alpha-MACPF reveals mechanism of membrane attack in complement immune defense. Science 317(5844):1552–1554

    CAS  PubMed  Google Scholar 

  • Humphrey JH, Dourmashkin RR (1969) The lesions in cell membranes caused by complement. Adv Immunol 11:75–115

    CAS  PubMed  Google Scholar 

  • Johnson TK, Crossman T, Foote KA, Henstridge MA, Saligari MJ, Forbes Beadle L, Herr A, Whisstock JC, Warr CG (2013) Torso-like functions independently of Torso to regulate Drosophila growth and developmental timing. Proc Natl Acad Sci U S A 110(36):14688–14692. doi:10.1073/pnas.1309780110

    Article  PubMed  PubMed Central  Google Scholar 

  • Kafsack BF, Carruthers VB (2010) Apicomplexan perforin-like proteins. Commun Integr Biol 3(1):18–23

    PubMed  PubMed Central  Google Scholar 

  • Kafsack BF, Pena JD, Coppens I, Ravindran S, Boothroyd JC, Carruthers VB (2009) Rapid membrane disruption by a perforin-like protein facilitates parasite exit from host cells. Science 323(5913):530–533

    CAS  PubMed  Google Scholar 

  • Karatekin E, Sandre O, Guitouni H, Borghi N, Puech PH, Brochard-Wyart F (2003) Cascades of transient pores in giant vesicles: line tension and transport. Biophys J 84(3):1734–1749. doi:10.1016/S0006-3495(03)74981-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Law RH, Lukoyanova N, Voskoboinik I, Caradoc-Davies TT, Baran K, Dunstone MA, D’Angelo ME, Orlova EV, Coulibaly F, Verschoor S, Browne KA, Ciccone A, Kuiper MJ, Bird PI, Trapani JA, Saibil HR, Whisstock JC (2010) The structural basis for membrane binding and pore formation by lymphocyte perforin. Nature 468(7322):447–451

    CAS  PubMed  Google Scholar 

  • Leung C, Dudkina NV, Lukoyanova N, Hodel AW, Farabella I, Pandurangan AP, Jahan N, Pires Damaso M, Osmanovic D, Reboul CF, Dunstone MA, Andrew PW, Lonnen R, Topf M, Saibil HR, Hoogenboom BW (2014) Stepwise visualization of membrane pore formation by suilysin, a bacterial cholesterol-dependent cytolysin. eLife 3. doi:10.7554/eLife.04247

  • Lopez JA, Susanto O, Jenkins MR, Lukoyanova N, Sutton VR, Law RH, Johnston A, Bird CH, Bird PI, Whisstock JC, Trapani JA, Saibil HR, Voskoboinik I (2013) Perforin forms transient pores on the target cell plasma membrane to facilitate rapid access of granzymes during killer cell attack. Blood 121(14):2659–2668. doi:10.1182/blood-2012-07-446146

    Article  CAS  PubMed  Google Scholar 

  • Lovelace LL, Cooper CL, Sodetz JM, Lebioda L (2011) Structure of human C8 protein provides mechanistic insight into membrane pore formation by complement. J Biol Chem 286(20):17585–17592. doi:10.1074/jbc.M111.219766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lukoyanova N, Kondos SC, Farabella I, Law RH, Reboul CF, Caradoc-Davies TT, Spicer BA, Kleifeld O, Traore DA, Ekkel SM, Voskoboinik I, Trapani JA, Hatfaludi T, Oliver K, Hotze EM, Tweten RK, Whisstock JC, Topf M, Saibil HR, Dunstone MA (2015) Conformational changes during pore formation by the perforin-related protein pleurotolysin. PLoS Biol 13(2):e1002049. doi:10.1371/journal.pbio.1002049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marchioretto M, Podobnik M, Dalla Serra M, Anderluh G (2013) What planar lipid membranes tell us about the pore-forming activity of cholesterol-dependent cytolysins. Biophys Chem 182:64–70. doi:10.1016/j.bpc.2013.06.015

    Article  CAS  PubMed  Google Scholar 

  • McCormack R, de Armas L, Shiratsuchi M, Podack ER (2013a) Killing machines: three pore-forming proteins of the immune system. Immunol Res 57(1–3):268–278. doi:10.1007/s12026-013-8469-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McCormack R, de Armas LR, Shiratsuchi M, Ramos JE, Podack ER (2013b) Inhibition of intracellular bacterial replication in fibroblasts is dependent on the perforin-like protein (perforin-2) encoded by macrophage-expressed gene 1. J Innate Immun 5(2):185–194. doi:10.1159/000345249

    Article  CAS  PubMed  Google Scholar 

  • Metkar SS, Wang B, Catalan E, Anderluh G, Gilbert RJ, Pardo J, Froelich CJ (2011) Perforin rapidly induces plasma membrane phospholipid flip-flop. PLoS One 6(9):e24286

    CAS  PubMed  PubMed Central  Google Scholar 

  • Metkar S, Marchioretto M, Antonini V, Lunelli L, Wang B, Gilbert RJC, Anderluh G, Roth R, Pooga M, Pardo J, Heuser JE, Dalla Serra M, Froelich CJ (2015) Perforin oligomers form arcs in cellular membranes: a locus for intracellular delivery of granzymes. Cell Death Differ 22:78–85

    Google Scholar 

  • Michaels DW, Abramovitz AS, Hammer CH, Mayer MM (1976) Increased ion permeability of planar lipid bilayer membranes after treatment with the C5b-9 cytolytic attack mechanism of complement. Proc Natl Acad Sci U S A 73(8):2852–2856

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mueller M, Grauschopf U, Maier T, Glockshuber R, Ban N (2009) The structure of a cytolytic alpha-helical toxin pore reveals its assembly mechanism. Nature 459(7247):726–730. doi:10.1038/nature08026

    Article  CAS  PubMed  Google Scholar 

  • Ojcius DM, Persechini PM, Zheng LM, Notaroberto PC, Adeodato SC, Young JD (1991) Cytolytic and ion channel-forming properties of the N terminus of lymphocyte perforin. Proc Natl Acad Sci U S A 88(11):4621–4625

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pardo J, Aguilo JI, Anel A, Martin P, Joeckel L, Borner C, Wallich R, Mullbacher A, Froelich CJ, Simon MM (2009) The biology of cytotoxic cell granule exocytosis pathway: granzymes have evolved to induce cell death and inflammation. Microbes Infect 11(4):452–459. doi:10.1016/j.micinf.2009.02.004

    Article  CAS  PubMed  Google Scholar 

  • Persechini PM, Ojcius DM, Adeodato SC, Notaroberto PC, Daniel CB, Young JD (1992) Channel-forming activity of the perforin N-terminus and a putative alpha-helical region homologous with complement C9. Biochemistry 31(21):5017–5021

    CAS  PubMed  Google Scholar 

  • Podack ER, Dennert G (1983) Assembly of two types of tubules with putative cytolytic function by cloned natural killer cells. Nature 302(5907):442–445

    CAS  PubMed  Google Scholar 

  • Podobnik M, Marchioretto M, Zanetti M, Bavdek A, Kisovec M, Cajnko MM, Lunelli L, Dalla Serra M, Anderluh G (2015) Plasticity of listeriolysin O pores and its regulation by pH and a unique histidine. Sci Rep 5:9623

    PubMed  PubMed Central  Google Scholar 

  • Praper T, Sonnen AF, Kladnik A, Andrighetti AO, Viero G, Morris KJ, Volpi E, Lunelli L, Dalla Serra M, Froelich CJ, Gilbert RJ, Anderluh G (2011a) Perforin activity at membranes leads to invaginations and vesicle formation. Proc Natl Acad Sci U S A 108(52):21016–21021

    CAS  PubMed  PubMed Central  Google Scholar 

  • Praper T, Sonnen AF, Viero G, Kladnik A, Froelich CJ, Anderluh G, Dalla Serra M, Gilbert RJ (2011b) Human perforin employs different avenues to damage membranes. J Biol Chem 286:2946–2955

    CAS  PubMed  Google Scholar 

  • Qian S, Wang W, Yang L, Huang HW (2008) Structure of transmembrane pore induced by Bax-derived peptide: evidence for lipidic pores. Proc Natl Acad Sci U S A 105(45):17379–17383. doi:10.1073/pnas.0807764105

    Article  PubMed  PubMed Central  Google Scholar 

  • Raghava S, Giorda KM, Romano FB, Heuck AP, Hebert DN (2013) SV40 late protein VP4 forms toroidal pores to disrupt membranes for viral release. Biochemistry 52(22):3939–3948. doi:10.1021/bi400036z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reboul CF, Whisstock JC, Dunstone MA (2014) A new model for pore formation by cholesterol-dependent cytolysins. PLoS Comput Biol 10(8):e1003791. doi:10.1371/journal.pcbi.1003791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roiko MS, Carruthers VB (2009) New roles for perforins and proteases in apicomplexan egress. Cell Microbiol 11(10):1444–1452

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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):1548–1551. doi:10.1126/science.1144706

    Article  CAS  PubMed  Google Scholar 

  • Rosado CJ, Kondos S, Bull TE, Kuiper MJ, Law RH, Buckle AM, Voskoboinik I, Bird PI, Trapani JA, Whisstock JC, Dunstone MA (2008) The MACPF/CDC family of pore-forming toxins. Cell Microbiol 10(9):1765–1774. doi:10.1111/j.1462-5822.2008.01191.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schlumberger S, Kristan KC, Ota K, Frangez R, Molgomicron J, Sepcic K, Benoit E, Macek P (2014) Permeability characteristics of cell-membrane pores induced by ostreolysin A/pleurotolysin B, binary pore-forming proteins from the oyster mushroom. FEBS Lett 588(1):35–40. doi:10.1016/j.febslet.2013.10.038

    Article  CAS  PubMed  Google Scholar 

  • Shatursky O, Heuck AP, Shepard LA, Rossjohn J, Parker MW, Johnson AE, Tweten RK (1999) The mechanism of membrane insertion for a cholesterol-dependent cytolysin: a novel paradigm for pore-forming toxins. Cell 99(3):293–299

    CAS  PubMed  Google Scholar 

  • Shepard LA, Heuck AP, Hamman BD, Rossjohn J, Parker MW, Ryan KR, Johnson AE, Tweten RK (1998) Identification of a membrane-spanning domain of the thiol-activated pore-forming toxin Clostridium perfringens perfringolysin O: an alpha-helical to beta-sheet transition identified by fluorescence spectroscopy. Biochemistry 37(41):14563–14574. doi:10.1021/bi981452f

    Article  CAS  PubMed  Google Scholar 

  • Shepard LA, Shatursky O, Johnson AE, Tweten RK (2000) The mechanism of pore assembly for a cholesterol-dependent cytolysin: formation of a large prepore complex precedes the insertion of the transmembrane beta-hairpins. Biochemistry 39(33):10284–10293

    CAS  PubMed  Google Scholar 

  • Shiver JW, Dankert JR, Esser AF (1991) Formation of ion-conducting channels by the membrane attack complex proteins of complement. Biophys J 60(4):761–769. doi:10.1016/S0006-3495(91)82110-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Solecki DJ (2012) Sticky situations: recent advances in control of cell adhesion during neuronal migration. Curr Opin Neurobiol 22(5):791–798. doi:10.1016/j.conb.2012.04.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sonnen AF, Henneke P (2014) Structural biology of the membrane attack complex. Subcell Biochem 80:83–116. doi:10.1007/978-94-017-8881-6_6

    Article  CAS  PubMed  Google Scholar 

  • Sonnen AF, Plitzko J, Gilbert RJC (2014) Incomplete pneumolysin oligomers form membrane pores. Roy Soc Open Biol 4:140044

    Google Scholar 

  • Spilsbury K, O’Mara MA, Wu WM, Rowe PB, Symonds G, Takayama Y (1995) Isolation of a novel macrophage-specific gene by differential cDNA analysis. Blood 85(6):1620–1629

    CAS  PubMed  Google Scholar 

  • Steringer JP, Bleicken S, Andreas H, Zacherl S, Laussmann M, Temmerman K, Contreras FX, Bharat TA, Lechner J, Muller HM, Briggs JA, Garcia-Saez AJ, Nickel W (2012) Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-dependent oligomerization of fibroblast growth factor 2 (FGF2) triggers the formation of a lipidic membrane pore implicated in unconventional secretion. J Biol Chem 287(33):27659–27669. doi:10.1074/jbc.M112.381939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stevens LM, Beuchle D, Jurcsak J, Tong X, Stein D (2003) The Drosophila embryonic patterning determinant torsolike is a component of the eggshell. Curr Biol 13(12):1058–1063

    CAS  PubMed  Google Scholar 

  • Stolfi RL (1968) Immune lytic transformation: a state of irreversible damage generated as a result of the reaction of the eighth component in the guinea pig complement system. J Immunol 100(1):46–54

    CAS  PubMed  Google Scholar 

  • Tanaka K, Caaveiro JM, Morante K, Gonzalez-Manas JM, Tsumoto K (2015) Structural basis for self-assembly of a cytolytic pore lined by protein and lipid. Nat Commun 6:6337. doi:10.1038/ncomms7337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tavares J, Formaglio P, Thiberge S, Mordelet E, Van Rooijen N, Medvinsky A, Menard R, Amino R (2013) Role of host cell traversal by the malaria sporozoite during liver infection. J Exp Med 210(5):905–915. doi:10.1084/jem.20121130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Teissie J, Golzio M, Rols MP (2005) Mechanisms of cell membrane electropermeabilization: a minireview of our present (lack of ?) knowledge. Biochim Biophys Acta 1724(3):270–280. doi:10.1016/j.bbagen.2005.05.006

    Article  CAS  PubMed  Google Scholar 

  • Thiery J, Keefe D, Saffarian S, Martinvalet D, Walch M, Boucrot E, Kirchhausen T, Lieberman J (2010) Perforin activates clathrin- and dynamin-dependent endocytosis, which is required for plasma membrane repair and delivery of granzyme B for granzyme-mediated apoptosis. Blood 115(8):1582–1593

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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):770–777

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tilley SJ, Orlova EV, Gilbert RJ, Andrew PW, Saibil HR (2005) Structural basis of pore formation by the bacterial toxin pneumolysin. Cell 121(2):247–256

    CAS  PubMed  Google Scholar 

  • Tschopp J (1984) Ultrastructure of the membrane attack complex of complement. Heterogeneity of the complex caused by different degree of C9 polymerization. J Biol Chem 259(12):7857–7863

    CAS  PubMed  Google Scholar 

  • Uellner R, Zvelebil MJ, Hopkins J, Jones J, MacDougall LK, Morgan BP, Podack E, Waterfield MD, Griffiths GM (1997) Perforin is activated by a proteolytic cleavage during biosynthesis which reveals a phospholipid-binding C2 domain. EMBO J 16(24):7287–7296. doi:10.1093/emboj/16.24.7287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Valcarcel CA, Dalla Serra M, Potrich C, Bernhart I, Tejuca M, Martinez D, Pazos F, Lanio ME, Menestrina G (2001) Effects of lipid composition on membrane permeabilization by sticholysin I and II, two cytolysins of the sea anemone Stichodactyla helianthus. Biophys J 80(6):2761–2774. doi:10.1016/S0006-3495(01)76244-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Voskoboinik I, Thia MC, Fletcher J, Ciccone A, Browne K, Smyth MJ, Trapani JA (2005) Calcium-dependent plasma membrane binding and cell lysis by perforin are mediated through its C2 domain: A critical role for aspartate residues 429, 435, 483, and 485 but not 491. J Biol Chem 280(9):8426–8434. doi:10.1074/jbc.M413303200

    Article  CAS  PubMed  Google Scholar 

  • Voskoboinik I, Smyth MJ, Trapani JA (2006) Perforin-mediated target-cell death and immune homeostasis. Nat Rev Immunol 6(12):940–952

    CAS  PubMed  Google Scholar 

  • Westphal D, Dewson G, Menard M, Frederick P, Iyer S, Bartolo R, Gibson L, Czabotar PE, Smith BJ, Adams JM, Kluck RM (2014) Apoptotic pore formation is associated with in-plane insertion of Bak or Bax central helices into the mitochondrial outer membrane. Proc Natl Acad Sci U S A 111(39):E4076–E4085. doi:10.1073/pnas.1415142111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wiens M, Korzhev M, Krasko A, Thakur NL, Perovic-Ottstadt S, Breter HJ, Ushijima H, Diehl-Seifert B, Muller IM, Muller WE (2005) Innate immune defense of the sponge Suberites domuncula against bacteria involves a MyD88-dependent signaling pathway. Induction of a perforin-like molecule. J Biol Chem 280(30):27949–27959. doi:10.1074/jbc.M504049200

    Article  CAS  PubMed  Google Scholar 

  • Wilson PM, Fryer RH, Fang Y, Hatten ME (2010) Astn2, a novel member of the astrotactin gene family, regulates the trafficking of ASTN1 during glial-guided neuronal migration. J Neurosci 30(25):8529–8540. doi:10.1523/JNEUROSCI.0032-10.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Young JD, Cohn ZA, Podack ER (1986a) The ninth component of complement and the pore-forming protein (perforin 1) from cytotoxic T cells: structural, immunological, and functional similarities. Science 233(4760):184–190

    CAS  PubMed  Google Scholar 

  • Young JD, Hengartner H, Podack ER, Cohn ZA (1986b) Purification and characterization of a cytolytic pore-forming protein from granules of cloned lymphocytes with natural killer activity. Cell 44(6):849–859

    CAS  PubMed  Google Scholar 

  • Young JD, Nathan CF, Podack ER, Palladino MA, Cohn ZA (1986c) Functional channel formation associated with cytotoxic T-cell granules. Proc Natl Acad Sci U S A 83(1):150–154

    CAS  PubMed  PubMed Central  Google Scholar 

  • Young JD, Podack ER, Cohn ZA (1986d) Properties of a purified pore-forming protein (perforin 1) isolated from H-2-restricted cytotoxic T cell granules. J Exp Med 164(1):144–155

    CAS  PubMed  Google Scholar 

  • Young LH, Joag SV, Zheng LM, Lee CP, Lee YS, Young JD (1990) Perforin-mediated myocardial damage in acute myocarditis. Lancet 336(8722):1019–1021

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Robert J. C. Gilbert .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Gilbert, R.J.C. (2015). Perforins. In: Delcour, A.H. (eds) Electrophysiology of Unconventional Channels and Pores. Springer Series in Biophysics, vol 18. Springer, Cham. https://doi.org/10.1007/978-3-319-20149-8_12

Download citation

Publish with us

Policies and ethics