Pore-forming toxin

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Structure of the α-hemolysin from S. aureus , top view and side view

A pore-forming toxin ( English pore-forming toxin , PFT) is a protein having a pore in certain biomembranes forms and as a toxin acts.

properties

Pore-forming toxins are exotoxins that are mostly produced by pathogenic bacteria , e.g. B. Clostridium septicum and Staphylococcus aureus . The toxic effect is mediated by the cytotoxic effect on mammalian cells, as the cell membranes of cells are perforated through the pores , whereupon the cytosol leaks, the homeostasis of the cell can no longer be maintained and necrosis and apoptosis occur. Due to the damage caused to the host, most of the pore-forming toxins are counted among the virulence factors . Pore-forming toxins are used by bacteria to increase their food supply, to change the environmental conditions and in some cases to avoid an immune reaction by destroying immune cells . Sometimes pore-forming toxins are produced by bacteria to combat other types of bacteria, e.g. B. the channel-forming subtypes of colicins and possibly also nisin . In contrast to pore-forming toxins, bacteriocins or the non-ribosomal peptides such. B. Polymyxine or Iturine, although destabilizing for biomembranes , but mostly too small to form an ion channel .

In addition to bacterial pore-forming toxins, pore-forming proteins are also produced by eukaryotes to ward off bacterial infections, e.g. B. Defensin and Sarcotoxin . Others serve as toxins in poisonous eukaryotes, e.g. B. Melittin in bee venom . Eukaryotic MACPF -like proteins occur in perforin and the C9 of the complement system as part of the immune defense. The pore-forming toxins with antimicrobial effects belong to the group of antimicrobial peptides .

Types

Bacterial pore-forming toxins are divided into different groups, which differ in terms of structure and mechanism of action:

  • α-pore-forming toxins, e.g. B. Cytolysin A
  • β-pore-forming toxins, e.g. B. α- hemolysin , PV- leukocidine .
  • Cholesterol-dependent cytolysins, e.g. B. Pneumolysin
  • Small pore-forming toxins, e.g. B. Gramicidin A.

Other membrane - damaging toxins without pore formation are also AB toxins (e.g. anthrax toxin ).

α-pore-forming toxins

α-PFT such as cytolysin A (synonym hemolysin E , silent hemolysin locus A ) occur in some strains of Escherichia coli (especially uropathogenic strains), Salmonella enterica and Shigella flexneri .

β-pore-forming toxins

Overlay of the structures of α-hemolysin (red) and PV-leukocidine (green). Presumably the dark green area in the leukocidine pops out so that it resembles the dark red area in the hemolysin.

The protein structure of β-PFTs is made up of β-sheets . α-Hemolysin and Leukozidin S are structurally related, as are Aerolysin and Clostridium ε-toxin.

β-PFT are proteins that are present as soluble monomers or pore-forming protein complexes. The head of the heptameric α-hemolysin protrudes from the membrane, while the stem lies in the lipid bilayer of the membrane. The stem consists of a fourteen -strand β-barrel , with two strands of each monomer. The Vibrio cholerae cytolysin is also heptameric. The Staphylococcus aureus γ-hemolysin forms an octameric pore made up of sixteen strands. The Panton-Valentine-Leukozidin S has a similar form as a monomer.

The binding of the monomers to one another and the insertion into the membrane takes place similarly to the cytolysins by aggregation at the periphery of the membrane, followed by a change in the protein folding and the insertion of the stem into the membrane by means of hydrophobic amino acids at the end of the stem.

Some β-PFTs such as the Clostridium ε toxin and the Clostridium perfringens enterotoxin (CPE) bind to receptors , presumably claudin in CPE, as well as probably GPI anchors or other glycosylations in the ε toxin. The receptor-mediated accumulation of the monomers favors the aggregation to form multimeric pores. CPE serve the bacteria to defend themselves against macrophages , to change the environmental conditions and to improve the food supply.

Cholesterol-dependent cytolysins

Cholesterol-dependent cytolysins (also thiol-activated cytolysins, English cholesterol-dependent cytolysin , CDC) are z. B. pneumolysin from Streptococcus pneumoniae , perfringolysin O from C. perfringens , listeriolysin O of Listeria monocytogenes , Ivanolysin from Listeria ivanovii , Seeligeriolysin from Listeria seeligeri , hemolysin from Bacillus cereus , alveolysin from Bacillus alvei , streptolysin O from pyogenes Streptococcus or tetanolysin from Clostridium tetani . They form pores up to 260 Å (26 nm) in diameter, consisting of between 30 and 44 monomers. The multimerization takes place peripherally on the cell membrane, whereupon an α-helix is rearranged in an amphipathic β-loop . CDC are related to the MACPF family of pore-forming proteins in eukaryotes, and both families presumably use the same mechanism.

Structure of Perfringolysin O and PluMACPF. In both proteins, α-helices (pink) penetrate the membrane.

Small pore-forming toxins

Gramicidins are non-ribosomally produced short proteins of around ten to fifteen amino acids (D- and L-amino acids), which can also form pores in biomembrane.

literature

Web links

Commons : Pore forming cytotoxic proteins  - Collection of pictures, videos and audio files

Individual evidence

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  2. ^ H. Lee, HY Kim: Lantibiotics, class I bacteriocins from the genus Bacillus. In: Journal of microbiology and biotechnology. Volume 21, Number 3, March 2011, ISSN  1738-8872 , pp. 229-235, PMID 21464591 .
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  5. ^ TJ Wiles, MA Mulvey: The RTX pore-forming toxin α-hemolysin of uropathogenic Escherichia coli: progress and perspectives. In: Future microbiology. Volume 8, Number 1, January 2013, pp. 73-84, ISSN  1746-0921 . doi: 10.2217 / fmb.12.131 . PMID 23252494 . PMC 3570152 (free full text).
  6. ↑ S. Hunt, J. Green, PJ Artymiuk: Hemolysin E (HlyE, ClyA, SheA) and related toxins. In: Advances in Experimental Medicine and Biology . Volume 677, 2010, pp. 116-126, ISSN  0065-2598 . PMID 20687485 .
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  8. ↑ Guillet V, Roblin P, Werner S, et al. : Crystal structure of leucotoxin S component: new insight into the Staphylococcal β-barrel pore-forming toxins . In: J. Biol. Chem. . 279, No. 39, September 2004, pp. 41028-37. doi : 10.1074 / jbc.M406904200 . PMID 15262988 .
  9. ↑ Parker MW, Buckley JT, Postma JP, et al. : Structure of the Aeromonas toxin proaerolysin in its water-soluble and membrane-channel states . In: Nature . 367, No. 6460, January 1994, pp. 292-5. doi : 10.1038 / 367292a0 . PMID 7510043 .
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  11. ^ S. De, R. Olson: Crystal structure of the Vibrio cholerae cytolysin heptamer reveals common features among disparate pore-forming toxins. In: Proceedings of the National Academy of Sciences . Volume 108, Number 18, May 2011, pp. 7385-7390, ISSN  1091-6490 . doi: 10.1073 / pnas.1017442108 . PMID 21502531 . PMC 3088620 (free full text).
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  13. ^ V. Guillet, P. Roblin, S. Werner, M. Coraiola, G. Menestrina, H. Monteil, G. Prévost, L. Mourey: Crystal structure of leucotoxin S component: new insight into the Staphylococcal beta-barrel pore- forming toxins. In: The Journal of biological chemistry. Volume 279, Number 39, September 2004, pp. 41028-41037, ISSN  0021-9258 . doi: 10.1074 / jbc.M406904200 . PMID 15262988 .
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