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1.C.4 The Aerolysin Channel-forming Toxin (Aerolysin) Family

The aerolysins are a closely related group of channel-forming toxins secreted by members of the family Aeromonas, important human and animal pathogens. They are activated by host and bacterial proteases which remove a C-terminal fragment of about 40 amino acyl residues. The activated monomeric toxin then binds to a receptor glycosyl phosphatidylinositol (GPI)-anchored protein on the surface of the target cell. Because GPI anchored proteins are incorporated into the envelope membrane of human immunodeficiency virus type I (HIV-1), aerolysin can neutralize the virus in a process that depends on channel formation. The dual chaperone role of the C-terminal propeptide of aerolysin participates in folding and oligomerization of the pore-forming toxin (Iacovache et al., 2011).

Membrane binding of the monomeric toxin promotes oligomerization to a stable heptamer (as is known for the homologous α-hemolysin (αHL) family (TC #1.C.3)). Heptamerization converts the protein from a soluble form to a membrane insertion-competent form, and the oligomer penetrates the membrane producing channels that destroy the permeability barrier of the membrane, thereby killing the cell. The membrane-associated channel-forming protein may comprise a β-barrel. The three-dimensional structure of the soluble form of aerolysin from the Gram-negative bacterium, Aeromonas hydrophila, has been determined by x-ray crystallography (2.8 Å resolution) (Parker et al., 1994, 1996). The closely related aerolysins are distantly related to many other toxins including the α-toxin of the Gram-positive bacterium, Clostridium septicum, enterolobin, a cytolysin of the plant, Enterolobium contortisiliquum, the ε-toxin of Clostridium perfringens (1.C.5.1.1), and the α-hemolysin of Staphylococcus aureus (1.C.3.1.1). Members of the aerolysin family are therefore found in both bacteria and eukaryotes.

Hydralysins (1.C.4.2.1) are β pore-forming toxins in cnidaria, venomous animals such as Hydra vulgaris, and Chlorohydra viridissima (Sher et al., 2005). These toxins induce immediate fast muscle contraction followed by flaccid paralysis when injected into blowfly larvae (Zhang et al., 2003). They have strong hemolytic activity against certain insect cells. Other toxins, including the pore-forming actinoporins, but not hydralysins, are stored in sting cells called nematocytes.

Hydralysins are similar in structure and activity to many bacterial and fungal toxins (Sher et al., 2005) but show little sequence similarity with them. The soluble monomers are rich in β-structure and bind to erythrocyte membranes to form pores with an inner diameter of about 1.2 nm (Sher et al., 2005). Cytolysis is cell type-specific suggesting the involvement of a specific receptor. These toxins share some motif similarity around the pore-forming domains of the toxins and are homologous to ε-toxin (1.C.5.1.1) and α-toxin (1.C.4.2.1). 

The binary toxin (Bin), produced by Lysinibacillus (Bacillus) sphaericus, is composed of BinA (42 kDa) and BinB (51 kDa) proteins, which are both required for full toxicity against Culex and Anopheles mosquito larvae. Specificity of Bin toxin is determined by the binding of BinB to a receptor present on the midgut epithelial membranes, while BinA is proposed to be a toxic component. Srisucharitpanit et al. 2014 determined the crystal structure of the active form of BinB at a resolution of 1.75 A. It possesses two distinct structural domains in its N- and C-termini. The globular N-terminal domain has a beta-trefoil scaffold which is a highly conserved architecture of some sugar binding lectins, suggesting a role of this domain in receptor-binding. The BinB beta-rich C-terminal domain shares similar three-dimensional folding with aerolysin type beta-pore forming toxins, despite a low sequence identity. The BinB structure, therefore, is a new member of the aerolysin-like toxin family, with probably similarities in the cytolytic mechanism that takes place via pore formation.

The generalized transport reaction catalyzed by members of the aerolysin family is:

small molecules (in) → small molecules (out)

 

 

This family belongs to the: Aerolysin Superfamily.

References associated with 1.C.4 family:

Abrami, L., M. Fivaz, and F.G. van der Goot. (2000). Adventures of a pore-forming toxin at the target cell surface. Trends Microbiol. 8:168-172. 10754575
Akiba, T., Y. Abe, S. Kitada, Y. Kusaka, A. Ito, T. Ichimatsu, H. Katayama, T. Akao, K. Higuchi, E. Mizuki, M. Ohba, R. Kanai, and K. Harata. (2009). Crystal structure of the parasporin-2 Bacillus thuringiensis toxin that recognizes cancer cells. J. Mol. Biol. 386: 121-133. 19094993
Cowell, S., W. Aschauer, H.J. Gruber, K.L. Nelson, and J.T. Buckley. (1997). The erythrocyte receptor for the channel-forming toxin aerolysin is a novel glycosylphosphatidylinositol-anchored protein. Mol. Microbiol. 25: 343-350. 9282746
Degiacomi, M.T., I. Iacovache, L. Pernot, M. Chami, M. Kudryashev, H. Stahlberg, F.G. van der Goot, and M. Dal Peraro. (2013). Molecular assembly of the aerolysin pore reveals a swirling membrane-insertion mechanism. Nat Chem Biol. [Epub: Ahead of Print] 23912165
Iacovache, I., M.T. Degiacomi, L. Pernot, S. Ho, M. Schiltz, M. Dal Peraro, and F.G. van der Goot. (2011). Dual chaperone role of the C-terminal propeptide in folding and oligomerization of the pore-forming toxin aerolysin. PLoS Pathog 7: e1002135. 21779171
Imagawa, T., Y. Dohi, and Y. Higashi. (1994). Cloning, nucleotide sequence and expression of a hemolysin gene of Clostridium septicum. FEMS Microbiol. Lett. 117: 287-292. 8200504
Knapp O., Maier E., Mkaddem SB., Benz R., Bens M., Chenal A., Geny B., Vandewalle A. and Popoff MR. (2010). Clostridium septicum alpha-toxin forms pores and induces rapid cell necrosis. Toxicon. 55(1):61-72. 19632260
Mancheño, J.M., H. Tateno, I.J. Goldstein, M. Martínez-Ripoll, and J.A. Hermoso. (2005). Structural analysis of the Laetiporus sulphureus hemolytic pore-forming lectin in complex with sugars. J. Biol. Chem. 280: 17251-17259. 15687495
Nguyen, D.H., Z. Liao, J.T. Buckley, and J.E.K. Hildreth. (1999). The channel-forming toxin aerolysin neutralizes human immunodeficiency virus type 1. Mol. Microbiol. 33: 659-666. 10417655
Parker, M.W., F.G. van der Goot, and J.T. Buckley. (1996). Aerolysin–the ins and outs of a model channel-forming toxin. Mol. Microbiol. 19: 205-212. 8825766
Parker, M.W., J.T. Buckley, J.P. Postma, A.D. Tucker, K. Leonard, F. Pattus, and D. Tsernoglou. (1994). Structure of the Aeromonas toxin proaerolysin in its water-soluble and membrane-channel states. Nature 367: 292-295. 7510043
Saier, M.H., Jr., B.H. Eng, S. Fard, J. Garg, D.A. Haggerty, W.J. Hutchinson, D.L. Jack, E.C. Lai, H.J. Liu, D.P. Nusinew, A.M. Omar, S.S. Pao, I.T. Paulsen, J.A. Quan, M. Sliwinski, T.-T. Tseng, S. Wachi, and G.B. Young. (1999). Phylogenetic characterization of novel transport protein families revealed by genome analyses. Biochim. Biophys. Acta 1422: 1-56. 10082980
Sher, D. and E. Zlotkin. (2009). A hydra with many heads: protein and polypeptide toxins from hydra and their biological roles. Toxicon 54: 1148-1161. 19306890
Sher, D., Y. Fishman, M. Zhang, M. Lebendiker, A. Gaathon, J.M. Mancheno, and E. Zlotkin. (2005). Hydralysins, a new category of β-pore-forming toxins in cnidaria. J. Biol. Chem. 280: 22847-2255. 15824108
Srisucharitpanit, K., M. Yao, B. Promdonkoy, S. Chimnaronk, I. Tanaka, and P. Boonserm. (2014). Crystal structure of BinB: A receptor binding component of the binary toxin from Lysinibacillus sphaericus. Proteins. [Epub: Ahead of Print] 24975613
Whisstock, J.C. and M.A. Dunstone. (2013). Structural biology: Torqueing about pores. Nat Chem Biol 9: 605-606. 24045807
Zhang, M., Y. Fishman, D. Sher, and E. Zlotkin. (2003). Hydralysin, a novel animal group-selective paralytic and cytolytic protein from a noncnidocystic origin in hydra. Biochemistry 42: 8939-8944. 12885226