Poneratoxin

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Poneratoxin
PDB 1g92 EBI.jpg
Identifiers
SymbolPoneratoxin
SCOP2 1G92 / SCOPe / SUPFAM
OPM superfamily 151
OPM protein 1g92

Poneratoxin is a paralyzing neurotoxic peptide made by the bullet ant Paraponera clavata . It prevents inactivation of voltage gated sodium channels and therefore blocks synaptic transmission in the central nervous system. [1] Specifically, poneratoxin acts on voltage gated sodium channels in skeletal muscle fibers, causing paralysis, and nociceptive fibers, causing pain. [2] It is rated as a 4 plus on the Schmidt sting pain index, the highest possible rating with that system, and its effects can cause waves of pain up to twelve hours after a single sting. [3] It is additionally being studied for its uses in biological insecticides. [4]

Contents

Mechanism of action

Schematic shows normal open and inactivated voltage-gated sodium channels on the left. Upon binding of poneratoxin, the sodium channel is forced to stay in the open state, unable to be inactivated. This leads to prolongation of action potentials, which is associated with the pain from bullet ant stings. Poneratoxin schematic.tif
Schematic shows normal open and inactivated voltage-gated sodium channels on the left. Upon binding of poneratoxin, the sodium channel is forced to stay in the open state, unable to be inactivated. This leads to prolongation of action potentials, which is associated with the pain from bullet ant stings.

Overall, poneratoxin disrupts normal function of voltage-gated sodium channels in both vertebrates and invertebrates. It causes repetitive firing and prolongation of action potentials, particularly in the central nervous system of insects. [4] The increase in signaling is what causes the intense pain from bullet ant stings. [5]

Poneratoxin is in an inactive state when stored in the ant venom reservoir due to the reservoir's acidic conditions, but it becomes toxic when activated via a multistep process. The combination of poneratoxin binding to a cell membrane (in order to act upon a voltage-gated sodium channel) and the movement from acidic conditions in the ant venom reservoir to basic conditions at the target site leads to poneratoxin undergoing a conformational change that activates it. [1]

Catterall et al. hypothesized that some polypeptide neurotoxins that modify voltage-gated channels function via a "voltage-sensor trapping" mechanism. The hypothesis states that neurotoxins similar to poneratoxin, such as alpha-scorpion toxins, act upon sodium channels via binding to the channels' receptor site 3, which normally affects the channels' ability to inactivate. Therefore, receptor site 3 neurotoxins often affect sodium channels by slowing or blocking inactivation. [2] [6] Normally, the region of the channel where neurotoxin receptor site 3 is undergoes a conformational change of an outward movement to lead to inactivation. Receptor site 3 neurotoxins are proposed to prevent this conformational change via interaction with acidic and hydrophobic amino acid residues at that site. [6]

When frog skeletal muscle fibers were exposed to poneratoxin, it was found that poneratoxin primarily affected voltage-dependent sodium channels by decreasing the peak sodium current and also inducing a slow sodium current. This combination resulted in the sodium channels activating at very negative potentials and deactivating very slowly, a phenomenon commonly seen in excitable tissues. [7] Poneratoxin is considered as a slow-acting agonist for smooth muscles. [8]

Structure

The poneratoxin peptide is stored in an inactive 25-residue peptide (amino acid sequence FLPLLILGSLLMTPPVIQAIHDAQR) in the venom reservoir of Paraponera clavata . The secondary structure is characterized by a helix-turn-helix motif: two alpha helices connected by a beta-turn.

Poneratoxin inserting into the plasma membrane. Blue regions are hydrophilic, and red regions are hydrophobic Poneratoxin 1.tif
Poneratoxin inserting into the plasma membrane. Blue regions are hydrophilic, and red regions are hydrophobic

The two alpha helices are formed by residues 3–9 at the N-terminus, and residues 17–24 at the C-terminus, and they are connected by the beta-turn at residues 11–16. From a three-dimensional perspective, this structure forms a preferential V-shape with the two helices undergoing loose non-covalent interactions with each other. [1] This is notable because of its structural similarity to other peptides that interact with the membrane, and indicates that poneratoxin will also interact with the membrane and thereby affect embedded voltage gated sodium channels. [9] Furthermore, the structure of the peptide shifts from a random coil to the structured helix-turn-helix when introduced to a lipid bilayer environment, which indicates that this motif is important for interacting with the membrane. [1]

The two alpha helices, however, have markedly different characteristics. The N-terminal alpha helix is apolar, containing a central hydrophobic core with hydrophilic residues at either end, and is uncharged. It is similar in structure to a transmembrane signal peptide, which implies that it will anchor at the membrane by burying the hydrophobic core within the bilayer. [1] In particular, the bulky and very hydrophobic phenylalanine residue is important for interacting with uncharged lipid bilayers, such as those composed of phosphatidylcholine. The C-terminal alpha helix is amphipathic with one side displaying polar and charged residues, and the other displaying non-polar residues, which drives insertion into the plasma membrane. [10] Specifically, the positively charged arginine and the non-polar alanine residues were both shown to be essential for poneratoxin potency. [2] See figure, where the hydrophobic (red) and hydrophilic (blue) regions of poneratoxin and the lipid bilayer align, demonstrating that the structure is evolved to insert into the membrane, which will promote interaction with the voltage gated sodium channels.

Toxicology

Many people consider a sting from a bullet ant to resemble the sensation of getting shot. Justin Schmidt, an entomologist who developed the Schmidt sting pain index, described it as "pure, intense, brilliant pain...like walking over flaming charcoal with a three-inch nail embedded in your heel," and considers the sting from a bullet ant to be the most painful insect sting he has experienced. [11] The pain from bullet ant stings can last for many hours, even up to 24 hours. Both the immense pain and the duration of the sting are due to the effects of poneratoxin. [5] In addition to the notorious pain, symptoms of stings from bullet ants (as well as stings from other ants of the genus Paraponera as well as the genus Dinoponera ) include fever, cold sweats, nausea, vomiting, lymphadenopathy and cardiac arrhythmias.[ citation needed ]

Toxicity assays have found that the LT50 of poneratoxin, delivered via injections of genetically engineered viruses, to S. frugiperda larvae, was at 131 hours post-injection. A dose of 105 pfu of poneratoxin was sufficient to kill the S. frugiperda larvae, and a dose of 10 ng could paralyze them. [1] Based on these experiments, scientists believe poneratoxin can make a good candidate as a bio-insecticide because of its neurotoxicity to other insects, making it capable of immobilizing or even killing insects infected with it. The making of a recombinant virus by engineering a baculovirus that expresses poneratoxin has been proposed. [1]

See also

Related Research Articles

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Paraponera clavata, commonly known as the bullet ant, is a species of ant named for its extremely painful sting. It inhabits humid lowland rainforests in Central and South America.

<span class="mw-page-title-main">Schmidt sting pain index</span> Pain scale for insect stings

The Schmidt sting pain index is a pain scale rating the relative pain caused by different hymenopteran stings. It is mainly the work of Justin O. Schmidt, a former entomologist at the Carl Hayden Bee Research Center in Arizona. Schmidt published a number of works on the subject, and claimed to have been stung by the majority of stinging Hymenoptera.

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<span class="mw-page-title-main">Agatoxin</span>

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<span class="mw-page-title-main">Scorpion toxin</span>

Scorpion toxins are proteins found in the venom of scorpions. Their toxic effect may be mammal- or insect-specific and acts by binding with varying degrees of specificity to members of the Voltage-gated ion channel superfamily; specifically, voltage-gated sodium channels, voltage-gated potassium channels, and Transient Receptor Potential (TRP) channels. The result of this action is to activate or inhibit the action of these channels in the nervous and cardiac organ systems. For instance, α-scorpion toxins MeuNaTxα-12 and MeuNaTxα-13 from Mesobuthus eupeus are neurotoxins that target voltage-gated Na+ channels (Navs), inhibiting fast inactivation. In vivo assays of MeuNaTxα-12 and MeuNaTxα-13 effects on mammalian and insect Navs show differential potency. These recombinants exhibit their preferential affinity for mammalian and insect Na+ channels at the α-like toxins' active site, site 3, in order to inactivate the cell membrane depolarization faster[6]. The varying sensitivity of different Navs to MeuNaTxα-12 and MeuNaTxα-13 may be dependent on the substitution of a conserved Valine residue for a Phenylalanine residue at position 1630 of the LD4:S3-S4 subunit or due to various changes in residues in the LD4:S5-S6 subunit of the Navs. Ultimately, these actions can serve the purpose of warding off predators by causing pain or to subdue predators.

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<span class="mw-page-title-main">Pandinus imperator (Pi3) toxin</span>

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<span class="mw-page-title-main">GiTx1</span>

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Protoxin-I, also known as ProTx-I, or Beta/omega-theraphotoxin-Tp1a, is a 35-amino-acid peptide neurotoxin extracted from the venom of the tarantula Thrixopelma pruriens. Protoxin-I belongs to the inhibitory cystine knot (ICK) family of peptide toxins, which have been known to potently inhibit voltage-gated ion channels. Protoxin-I selectively blocks low voltage threshold T-type calcium channels, voltage gated sodium channels and the nociceptor cation channel TRPA1. Due to its unique ability to bind to TRPA1, Protoxin-I has been implicated as a valuable pharmacological reagent with potential applications in clinical contexts with regards to pain and inflammation

<span class="mw-page-title-main">Versutoxin</span>

Delta hexatoxin Hv1 is a neurotoxic component found in the venom of the Australian funnel web spider.

<span class="mw-page-title-main">GsMTx-4</span> Grammostola mechanotoxin 4

Grammostola mechanotoxin #4, also known as M-theraphotoxin-Gr1a (M-TRTX-Gr1a), is a neurotoxin isolated from the venom of the spider Chilean rose tarantula Grammostola spatulate. This amphiphilic peptide, which consists of 35 amino acids, belongs to the inhibitory cysteine knot (ICK) peptide family. It reduces mechanical sensation by inhibiting mechanosensitive channels (MSCs).

References

  1. 1 2 3 4 5 6 7 Szolajska E, Poznanski J, Ferber ML, Michalik J, Gout E, Fender P, Bailly I, Dublet B, Chroboczek J (June 2004). "Poneratoxin, a neurotoxin from ant venom. Structure and expression in insect cells and construction of a bio-insecticide". European Journal of Biochemistry. 271 (11): 2127–36. doi: 10.1111/j.1432-1033.2004.04128.x . PMID   15153103.
  2. 1 2 3 Johnson SR, Rikli HG, Schmidt JO, Evans MS (December 2017). "A reexamination of poneratoxin from the venom of the bullet ant Paraponera clavata". Peptides. 98: 51–62. doi:10.1016/j.peptides.2016.05.012. PMID   27266841. S2CID   23620280.
  3. ↑ Conniff R (2009-08-10). "Oh, Sting, Where Is Thy Death?". newyorktimes.com. Retrieved 26 April 2017.
  4. 1 2 Touchard A, Aili SR, Fox EG, Escoubas P, Orivel J, Nicholson GM, Dejean A (January 2016). "The Biochemical Toxin Arsenal from Ant Venoms". Toxins. 8 (1): 30. doi: 10.3390/toxins8010030 . PMC   4728552 . PMID   26805882.
  5. 1 2 Sullivan, Cody (16 July 2015). "This ant's sting is so bad it feels like getting shot — some call it the worst pain known to man". Business Insider.
  6. 1 2 Catterall WA, Cestèle S, Yarov-Yarovoy V, Yu FH, Konoki K, Scheuer T (February 2007). "Voltage-gated ion channels and gating modifier toxins" (PDF). Toxicon. 49 (2): 124–41. doi:10.1016/j.toxicon.2006.09.022. PMID   17239913. S2CID   5727158.
  7. ↑ Duval A, Malécot CO, Pelhate M, Piek T (March 1992). "Poneratoxin, a new toxin from an ant venom, reveals an interconversion between two gating modes of the Na channels in frog skeletal muscle fibres". Pflügers Archiv. 420 (3–4): 239–47. doi:10.1007/BF00374453. PMID   1317947. S2CID   166850.
  8. ↑ Piek T, Duval A, Hue B, Karst H, Lapied B, Mantel P, Nakajima T, Pelhate M, Schmidt JO (1991). "Poneratoxin, a novel peptide neurotoxin from the venom of the ant, Paraponera clavata". Comparative Biochemistry and Physiology. C, Comparative Pharmacology and Toxicology. 99 (3): 487–95. doi:10.1016/0742-8413(91)90276-y. PMID   1685425.
  9. ↑ Wang G, Sparrow JT, Cushley RJ (November 1997). "The helix-hinge-helix structural motif in human apolipoprotein A-I determined by NMR spectroscopy". Biochemistry. 36 (44): 13657–66. doi:10.1021/bi971151q. PMID   9354635.
  10. ↑ Drin G, Antonny B (May 2010). "Amphipathic helices and membrane curvature". FEBS Letters. 584 (9): 1840–7. doi: 10.1016/j.febslet.2009.10.022 . PMID   19837069.
  11. ↑ Loria K (23 August 2016). "A man who has been stung more than 1,000 times reveals the one bug you really want to avoid". Business Insider.
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