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

small molecules (in) small molecules (out)