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. 2019 Jun 25;11(6):370.
doi: 10.3390/toxins11060370.

Pore-Forming Proteins from Cnidarians and Arachnids as Potential Biotechnological Tools

Esperanza Rivera-de-Torre  1 , Juan Palacios-Ortega  2   3 , José G Gavilanes  4 , Álvaro Martínez-Del-Pozo  5 , Sara García-Linares  6
Affiliations

Pore-Forming Proteins from Cnidarians and Arachnids as Potential Biotechnological Tools

Esperanza Rivera-de-Torre et al. Toxins (Basel). .

Abstract

Animal venoms are complex mixtures of highly specialized toxic molecules. Cnidarians and arachnids produce pore-forming proteins (PFPs) directed against the plasma membrane of their target cells. Among PFPs from cnidarians, actinoporins stand out for their small size and molecular simplicity. While native actinoporins require only sphingomyelin for membrane binding, engineered chimeras containing a recognition antibody-derived domain fused to an actinoporin isoform can nonetheless serve as highly specific immunotoxins. Examples of such constructs targeted against malignant cells have been already reported. However, PFPs from arachnid venoms are less well-studied from a structural and functional point of view. Spiders from the Latrodectus genus are professional insect hunters that, as part of their toxic arsenal, produce large PFPs known as latrotoxins. Interestingly, some latrotoxins have been identified as potent and highly-specific insecticides. Given the proteinaceous nature of these toxins, their promising future use as efficient bioinsecticides is discussed throughout this Perspective. Protein engineering and large-scale recombinant production are critical steps for the use of these PFPs as tools to control agriculturally important insect pests. In summary, both families of PFPs, from Cnidaria and Arachnida, appear to be molecules with promising biotechnological applications.

Keywords: actinoporin; bioinsecticides; immunotoxin; latrotoxin; pore-forming proteins; transcriptomics; venomics.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Piercing delivery systems cross the skin, the first barrier encountered by venom (A). Specific extra-cellular matrix proteases, like metalloproteases, digest scaffold proteins (B). Non-proteinaceous components, like serotonin, promote vasodilatation (C). The plasma membrane is the most widespread structure in nature and, therefore, a suitable target of attack by enzymes like phospholipases or cytolysins (D). Neurotoxins interact with membrane receptors and channels, leading to imbalance in ion distribution across the membrane (E). Some toxins develop their harmful effects once they are internalized, blocking protein production or oxidative respiration in mitochondria (F). This image was created using Servier Medical Art free images database (SERVIER, Paris, France).
Figure 2
Figure 2
(A) Actinoporin monomers share a common fold: a stranded β-sandwich flanked by two short α-helixes. With regard to pore structure, two models have been proposed: (B) a tetrameric structure in which the lipid membrane adopts a toroidal shape around the pore walls, and (C) an octameric lipid-protein mixed structure in which lipids (in tan color) are accommodated in pore-wall fenestrations (see inserts on the right).
Figure 3
Figure 3
(A) Latrotoxins are produced as inactive precursor activated upon proteolytic digestion in both the N- and C-termini. The genetic structure comprises a unique N-terminal domain and a C-terminal domain rich in ankyrin repeats. Within a low-resolution three-dimensional structure of α-LTX obtained by cryo-EM, three different domains can be differentiated: the wing (pink), the body (green), and the head (yellow). (B) The final pore is composed by four α-LTX monomers, combined in a so called ‘four-bladed propeller’. The head and the body are responsible for membrane binding and pore formation, while the wing seems to be implicated in receptor recognition. Reproduced from Ushkaryov, Y.A., Volynski, K.E., Ashton, A.C., The multiple actions of black widow spider toxins and their selective use in neurosecretion studies. Toxicon 2004, Elsevier.
Figure 3
Figure 3
(A) Latrotoxins are produced as inactive precursor activated upon proteolytic digestion in both the N- and C-termini. The genetic structure comprises a unique N-terminal domain and a C-terminal domain rich in ankyrin repeats. Within a low-resolution three-dimensional structure of α-LTX obtained by cryo-EM, three different domains can be differentiated: the wing (pink), the body (green), and the head (yellow). (B) The final pore is composed by four α-LTX monomers, combined in a so called ‘four-bladed propeller’. The head and the body are responsible for membrane binding and pore formation, while the wing seems to be implicated in receptor recognition. Reproduced from Ushkaryov, Y.A., Volynski, K.E., Ashton, A.C., The multiple actions of black widow spider toxins and their selective use in neurosecretion studies. Toxicon 2004, Elsevier.
Figure 4
Figure 4
(A) Immunotoxins (IMTXs) are chimeric molecules composed of a monoclonal antibody that recognizes the malign cells and a toxin moiety that kills the targeted cells. (B) In order to improve the specificity of actinoporin IMTXs, protease-activated variants have been designed. Once the chimeric molecule binds specifically to malign cells (in purple) by recognition of a membrane motif missing in the healthy ones (in orange) (1), the toxic moiety is activated by a tumor specific protease (2). The activated actinoporin is then able to bind the membrane, oligomerize with other monomers, and form a pore, killing the targeted cell by an osmotic shock (3). This image was created using Servier Medical Art free images database (SERVIER, Paris, France).
Figure 5
Figure 5
Bioinsecticides can be spread over crops as aerosols if they are orally active, or they can enter their target through insect spiracles. Bioinsecticides can be delivered directly as active toxic products (A) or as genetically modified baculovirus-based pesticides, containing toxin genes (B). After larvae ingest baculoviruses by feeding, they can develop a lethal disease, releasing new infective particles, suitable for horizontal (dashed arrow) or vertical (continuous arrow) infection. Genetically modified crops for biopesticide production eliminate the pest in both adult and larva state if they are orally active (C). This image was created using Servier Medical Art free images database (SERVIER, Paris, France).
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