Pore‐forming Toxins


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: α‐PFT and β‐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 α‐PFT and β‐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 α‐PFT ClyA and its assembled pore. (a) Soluble monomeric toxin (1QOY) with the β‐tongue in cyan and the α‐helical pore‐forming domain in blue. (b) ClyA dodecameric assembly (2WCD) with a protomer in black and its β‐tongue and pore‐forming domain highlighted in cyan and blue, respectively. The rearrangement of the β‐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 α‐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 β‐hairpin pore‐forming domain in blue. Central panel: Structures of staphylococal β‐PFT. (c) Soluble γ‐hemolysin (2QK7 chain B) with the pore‐forming domain in blue. (d) α‐Hemolysin heptameric β‐barrel pore (7AHL) with a protomer highlighted in black and its β‐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+), (ATP) and proteins.



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Further Reading

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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]