Pore‐forming Toxins

Mauro Dalla Serra, Consiglio Nazionale delle Ricerche & Fondazione Bruno Kessler Trento, Italy
Mayra Tejuca Martínez, Universidad de La Habana Ciudad de La Habana, Cuba

Published online: December 2011

DOI: 10.1002/9780470015902.a0002655.pub2

Pore-forming toxins (PFT) are proteins able to produce well-structured holes in target cell membrane. They have a very broad taxonomic distribution being produced from bacteria to mammals. Depending on the secondary structure of the membrane-spanning region, these proteins are categorised into two classes: -PFT and -PFT. The pore structure of representative members of each class will be described. These proteins can be also classified according to their pore structure: barrel-stave and toroidal protein–lipid pore. In the barrel-stave pore the protein molecules provide a continuous interface between the core of the bilayer and the channel lumen, whereas in the toroidal protein–lipid pore both polypeptide chains and polar phospholipid headgroups are involved in the building of pore walls. The stoichiometry and the pore diameter depend on the protein, thus the channels can allow leakage of ions, adenosine triphosphate (ATP), proteins and even bacteria. Attacked cells trigger different responses, some promoting recovery of membrane integrity, others transition to a low-energy-consumption state, in addition to inflammatory responses and changes in gene transcription.

Key Concepts:

  • Pore-forming toxins are proteins produced from bacteria to mammals.
  • Pore-forming toxins are classified as -PFT and -PFT, according to the structure adopted by the transmembrane region.
  • Pores are nanometre funnel-like holes that permit the passage of water, ions and small molecules through cell membranes.
  • PFT form two types of pores, the barrel-stave and the toroidal protein–lipid pore.
  • Cells react to pore formation, repair the damage and survive.

Keywords: ion channels; pores; cytolysins; membrane insertion; pore-forming toxins

Figure 1. Upper panel: Structures of the soluble -PFT ClyA and its assembled pore. (a) Soluble monomeric toxin (1QOY) with the -tongue in cyan and the -helical pore-forming domain in blue. (b) ClyA dodecameric assembly (2WCD) with a protomer in black and its -tongue and pore-forming domain highlighted in cyan and blue, respectively. The rearrangement of the -tongue and the movement of the pore-forming domain can be seen by comparison between the soluble and the dodecameric assembled structure. Lower panel: (c) Water-soluble form of the actinoporin sticholysin II (1GWY), an -PFT. The pore-forming domain is highlighted in blue.
Figure 2. Upper panel: Structure of soluble VCC and its assembled pore. (a) Soluble VCC protoxin (1XEZ) with the prodomain in magenta, the cradle loop in yellow and the pore-forming domain in blue. The carboxy-terminal lectin domains are labelled. (b) VCC assembled heptamer (3O44) with a protomer highlighted in black and its -hairpin pore-forming domain in blue. Central panel: Structures of staphylococal -PFT. (c) Soluble -hemolysin (2QK7 chain B) with the pore-forming domain in blue. (d) -Hemolysin heptameric -barrel pore (7AHL) with a protomer highlighted in black and its -hairpin pore-forming domain in blue. Lower panel: (e) Water-soluble form of the CDC perfringolysin O (1PFO). The insertion peptide is highlighted in blue.
Figure 3. Schematic structures of three different types of membrane pores: (a) Barrel-stave pores, (b) toroidal protein–lipid pores and (c) arc-shaped pores. Each cylinder represents the pore-forming domain of an individual protein.
Figure 4. Steps leading to the formation of PFT channels. (1) Soluble monomers reach the target membrane. (2, 3) Toxin monomers bind to the cell membrane. Particular membrane components (2) or regions with peculiar lipid composition (3) may enhance binding affinity. (4) Toxin monomers oligomerise, via lateral diffusion on the cell surface, and (may) form a nonpenetrating pre-pore intermediate (5). The oligomer inserts an amphipathic section into the lipid matrix, generating a transmembrane channel (6) that allows leakage of ions (mainly influx of Na+ and Ca2+ and efflux of K+), adenosine triphosphate (ATP) and proteins.
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 References
    Aguilar JL, Kulkarni R, Randis TM et al. (2009) Phosphatase-dependent regulation of epithelial mitogen-activated protein kinase responses to toxin-induced membrane pores. PLoS ONE 4(11): e8076.
    Alvarez C, Dalla Serra M, Potrich C et al. (2001) Effects of lipid composition on membrane permeabilization by sticholysin I and II, two cytolysins of the sea anemone Stichodactyla helianthus. Biophysical Journal 80(June): 2761–2774.
    Anderluh G, Dalla Serra M, Viero G et al. (2003) Pore formation by equinatoxin II, an eukaryotic protein toxin, occurs by induction of non-lamellar lipid structures. Journal of Biological Chemistry 278: 45216–45223.
    Aroian R and van der Goot FG (2007) Pore-forming toxins and cellular non-immune defenses (CNIDs). Current Opinion in Microbiology 10(1): 57–61.
    Athanasiadis A, Anderluh G, Macek P et al. (2001) Crystal structure of the soluble form of equinatoxin II, a pore-forming toxin from the sea anemone Actinia equina. Structure 9: 341–346.
    Bernheimer AW and Rudy B (1986) Interactions between membranes and cytolytic peptides. Biochimica et Biophysica Acta – Biomembranes 864: 123–141.
    Bischofberger M, Gonzalez MR and van der Goot FG (2009) Membrane injury by pore-forming proteins. Current Opinion in Cell Biology 21(4): 589–595.
    Collier RJ (2009) Membrane translocation by anthrax toxin. Molecular Aspects of Medicine 30(6): 413–422.
    Czajkowsky DM, Hotze EM, Shao Z et al. (2004) Vertical collapse of a cytolysin prepore moves its transmembrane beta-hairpins to the membrane. EMBO Journal 23(16): 3206–3215.
    De S and Olson R (2011) Crystal structure of the Vibrio cholerae cytolysin heptamer reveals common features among disparate pore-forming toxins. Proceedings of the National Academy of Sciences of the USA 108(18): 7385–7390.
    Epand RF, Martinou JC, Montessuit S et al. (2003) Transbilayer lipid diffusion promoted by Bax: implications for apoptosis. Biochemistry 42(49): 14576–14582.
    Galdiero S and Gouaux E (2004) High resolution crystallographic studies of alpha-hemolysin–phospholipid complexes define heptamer-lipid head group interactions: implication for understanding protein–lipid interactions. Protein Science 13(6): 1503–1511.
    Gilbert RJ (2010) Cholesterol-dependent cytolysins. Advances in Experimental Medicine and Biology 677: 56–66.
    Gonzalez MR, Bischofberger M, Freche B et al. (2011) Pore-forming toxins induce multiple cellular responses promoting survival. Cellular Microbiology 13(7): 1026–1043.
    Gray JV, Petsko GA, Johnston GC et al. (2004) Sleeping beauty: quiescence in Saccharomyces cerevisiae. Microbiology and Molecular Biology Reviews 68(2): 187–206.
    Gurcel L, Abrami L, Girardin S et al. (2006) Caspase-1 activation of lipid metabolic pathways in response to bacterial pore-forming toxins promotes cell survival. Cell 126(6): 1135–1145.
    Gutierrez MG, Saka HA, Chinen I et al. (2007) Protective role of autophagy against Vibrio cholerae cytolysin, a pore-forming toxin from V. cholerae. Proceedings of the National Academy of Sciences of the USA 104(6): 1829–1834.
    Gutierrez-Aguirre I, Barlic A, Podlesek Z et al. (2004) Membrane insertion of the N-terminal alpha-helix of equinatoxin II, a sea anemone cytolytic toxin. Biochemical Journal 384: 421–428.
    Hamon MA, Batsche E, Regnault B et al. (2007) Histone modifications induced by a family of bacterial toxins. Proceedings of the National Academy of Sciences of the USA 104(33): 13467–13472.
    Heuck AP, Tweten RK and Johnson AE (2001) Beta-barrel pore-forming toxins: intriguing dimorphic proteins. Biochemistry 40(31): 9065–9073.
    Hinds MG, Zhang W, Anderluh G et al. (2002) Solution structure of the eukaryotic pore-forming cytolysin equinatoxin II: implications for pore formation. Journal of Molecular Biology 315(5): 1219–1229.
    Holbourn KP, Shone CC and Acharya KR (2006) A family of killer toxins. Exploring the mechanism of ADP-ribosylating toxins. FEBS Journal 273(20): 4579–4593.
    Huffman DL, Abrami L, Sasik R et al. (2004) Mitogen-activated protein kinase pathways defend against bacterial pore-forming toxins. Proceedings of the National Academy of Sciences of the USA 101(30): 10995–11000.
    Husmann M, Beckmann E, Boller K et al. (2009) Elimination of a bacterial pore-forming toxin by sequential endocytosis and exocytosis 1. FEBS Letters 583(2): 337–344.
    Husmann M, Dersch K, Bobkiewicz W et al. (2006) Differential role of p38 mitogen activated protein kinase for cellular recovery from attack by pore-forming S. aureus alpha-toxin or streptolysin O. Biochemical and Biophysical Research Communications 344(4): 1128–1134.
    Idone V, Tam C, Goss JW et al. (2008) Repair of injured plasma membrane by rapid Ca2+-dependent endocytosis. Journal of Cell Biology 180(5): 905–914.
    Kennedy CL, Smith DJ, Lyras D et al. (2009) Programmed cellular necrosis mediated by the pore-forming alpha-toxin from Clostridium septicum. PLoS Pathogens 5(7): e1000516.
    Kepp O, Galluzzi L, Zitvogel L et al. (2010) Pyroptosis – a cell death modality of its kind? European Journal of Immunology 40(3): 627–630.
    Kloft N, Busch T, Neukirch C et al. (2009) Pore-forming toxins activate MAPK p38 by causing loss of cellular potassium. Biochemical and Biophysical Research Communications 385(4): 503–506.
    Mancheno JM, Martin-Benito J, Martinez-Ripoll M et al. (2003) Crystal and electron microscopy structures of sticholysin II actinoporin reveal insights into the mechanism of membrane pore formation. Structure 11(11): 1319–1328.
    Mechaly AE, Bellomio A, Gil-Carton D et al. (2011) Structural insights into the oligomerization and architecture of eukaryotic membrane pore-forming toxins. Structure 19(2): 181–191.
    Mestre MB, Fader CM, Sola C et al. (2010) Alpha-hemolysin is required for the activation of the autophagic pathway in Staphylococcus aureus-infected cells. Autophagy 6(1): 110–125.
    Meyer-Morse N, Robbins JR, Rae CS et al. (2010) Listeriolysin O is necessary and sufficient to induce autophagy during Listeria monocytogenes infection. PLoS ONE 5(1): e8610.
    Morgan PJ, Hyman SC, Byron O et al. (1994) Modeling the bacterial protein toxin, pneumolysin, in its monomeric and oligomeric form. The Journal of Biological Chemistry 269(41): 25315–25320.
    Mueller M, Grauschopf U, Maier T et al. (2009) The structure of a cytolytic -helical toxin pore reveals its assembly mechanism. Nature 459: 726–730.
    Nelson KL, Brodsky RA and Buckley JT (1999) Channels formed by subnanomolar concentrations of the toxin aerolysin trigger apoptosis of T lymphomas. Cellular Microbiology 1(1): 69–74.
    Nguyen KT, Le Clair SV, Ye S et al. (2009) Molecular interactions between magainin 2 and model membranes in situ. Journal of Physical Chemistry B 113(36): 12358–12363.
    Olson R and Gouaux E (2005) Crystal structure of the Vibrio cholerae cytolysin (VCC) pro-toxin and its assembly into a heptameric transmembrane pore. Journal of Molecular Biology 350(5): 997–1016.
    Palmer M, Harris R, Freytag C et al. (1998) Assembly mechanism of the oligomeric streptolysin O pore: the early membrane lesion is lined by a free edge of the lipid membrane and is extended gradually during oligomerization. EMBO Journal 17(6): 1598–1605.
    Praper T, Sonnen A, Viero G et al. (2011) Human perforin employs different avenues to damage membranes. Journal of Biological Chemistry 286(4): 2946–2955.
    book Prévost G, Mourey L, Colin DA et al. (2005) "Alpha-helix and beta-barrel pore-forming toxins (leucocidins, alpha-, gamma- and delta-cytolysins) of Staphylococcus aureus". In: Alouf JE and Freer JH (eds) The Comprehensive Sourcebook of Bacterial Protein Toxins, 588–605. Amsterdam: Academic Press.
    Qian S, Wang W, Yang L et al. (2008) Structure of transmembrane pore induced by Bax-derived peptide: evidence for lipidic pores. Proceedings of the National Academy of Sciences of the USA 105(45): 17379–17383.
    Rapson AC, Hossain MA, Wade JD et al. (2011) Structural dynamics of a lytic peptide interacting with a supported lipid bilayer. Biophysical Journal 100(5): 1353–1361.
    Ratner AJ, Hippe KR, Aguilar JL et al. (2006) Epithelial cells are sensitive detectors of bacterial pore-forming toxins. Journal of Biological Chemistry 281(18): 12994–12998.
    Rosado CJ, Kondos S, Bull TE et al. (2008) The MACPF/CDC family of pore-forming toxins. Cellular Microbiology 10(9): 1765–1774.
    Saha N and Banerjee KK (1997) Carbohydrate-mediated regulation of interaction of Vibrio cholerae hemolysin with erythrocyte and phospholipid vesicle. Journal of Biological Chemistry 272(1): 162–167.
    Sobko AA, Kotova EA, Antonenko YN et al. (2006) Lipid dependence of the channel properties of a colicin E1-lipid toroidal pore. Journal of Biological Chemistry 281(20): 14408–14416.
    Song L, Hobaugh MR, Shustak C et al. (1996) Structure of staphylococcal alpha-hemolysin, a heptameric transmembrane pore. Science 274: 1859–1866.
    Viala JP, Mochegova SN, Meyer-Morse N et al. (2008) A bacterial pore-forming toxin forms aggregates in cells that resemble those associated with neurodegenerative diseases. Cellular Microbiology 10(4): 985–993.
    Viero G, Gropuzzo A, Joubert O et al. (2008) A molecular pin to study the dynamic of b-barrel formation in pore forming toxins on erythrocytes: a sliding model. Cellular and Molecular Life Sciences 65(2): 312–323.
    Wallace AJ, Stillman TJ, Atkins A et al. (2000) E-coli hemolysin E (HlyE, ClyA, SheA): X-ray crystal structure of the toxin and observation of membrane pores by electron microscopy. Cell 100(2): 265–276.
    Yamashita K, Kawai Y, Tanaka Y et al. (2011) Crystal structure of the octameric pore of staphylococcal -hemolysin reveals the -barrel pore formation mechanism by two components. Proceedings of the National Academy of Sciences of the United States of America 108(42): 17314–17319.
 Further Reading
    book Alouf JE and Popoff MR (2006) The Comprehensive Soucebook of Bacterial Protein Toxins. Amsterdam: Academic Press.
    Anderluh G and Lakey JH (2008) Disparate proteins use similar architectures to damage membranes. Trends in Biochemical Sciences 33: 482–490.
    Bayley H (2009) Piercing insights. Nature 459: 651–652.
    Iacovache I, Bischofberger M and van der Goot FG (2010) Structure and assembly of pore-forming proteins. Current Opinion in Structural Biology 20: 241–246.
    book Menestrina G, Dalla Serra M and Lazarovici P (2003) Pore-forming Peptides and Protein Toxins. London, UK: Taylor & Francis Group.
    Parker MW and Feil SC (2005) Pore-forming protein toxins: from structure to function. Progress in Biophysics & Molecular Biology 88: 91–142.

Related Sub-Topics:

Cell Membranes | Cell Death and Cellular Senescence | Membrane Proteins | Medical Microbiology
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Article Title: Pore‐forming Toxins
 
How to Cite close
Dalla Serra, Mauro, and Tejuca Martínez, Mayra(Dec 2011) Pore‐forming Toxins. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0002655.pub2]