Scorpion toxin

Last updated
Scorpion long-chain toxin
Scorpiontoxinproteinimage.png
Crystal structure of toxin II from the scorpion Androctonus australis Hector. [1]
Identifiers
SymbolToxin_3
Pfam PF00537
InterPro IPR002061
SCOP2 2sn3 / SCOPe / SUPFAM
TCDB 8.B.1
OPM superfamily 58
OPM protein 1djt
Scorpion short toxin
1agt.png
Agitoxin-2. Disulphide bonds are highlighted. PDB 1agt [2]
Identifiers
SymbolToxin_2
Pfam PF00451
Pfam clan CL0054
InterPro IPR001947
PROSITE PDOC00875
TCDB 8.B.2
OPM superfamily 58
OPM protein 1ne5

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, [3] and Transient Receptor Potential (TRP) channels. [4] [5] 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 (MeuNaTxα-12 and MeuNaTxα-13) 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. [6] Ultimately, these actions can serve the purpose of warding off predators by causing pain (e.g., through the activation of sodium channels or TRP channels in sensory neurons) [7] or to subdue predators (e.g., in the case of inhibition of cardiac ion channels). [8]

Contents

The family includes related short- and long-chain scorpion toxins. It also contains a group of proteinase inhibitors from the plants Arabidopsis thaliana and Brassica spp.

The Brassica napus (oil seed rape) and Sinapis alba (white mustard) inhibitors, [9] [10] inhibit the catalytic activity of bovine beta-trypsin and bovine alpha-chymotrypsin, which belong to MEROPS peptidase family S1 (InterPro :  IPR001254 ). [11]

This group of proteins is now used in the creation of insecticides, vaccines, and protein engineering scaffolds.

Structure

The complete covalent structure of several such toxins has been deduced: They comprise around 66 amino acid residues forming a three stranded anti-parallel beta sheet over which lies an alpha helix of approximately three turns. Four disulfide bridges cross-link the structure of the long-chain toxins whereas the short toxins contain only three. [12] [13] BmKAEP, an anti-epilepsy peptide isolated from the venom of the Manchurian scorpion, [14] shows similarity to both scorpion neurotoxins and anti-insect toxins.

Function

The toxin's molecular function is to inhibit ion channels. The two types of Na+ channel toxins can be divided into two groups (alpha and beta) based on their functional effects. Beta (β) toxins shift the voltage-dependence of activation to more negative potentials, making the channel more likely to open at membrane potentials where activation would normally not occur. Alpha (α) toxins inhibit the fast inactivation mechanism, prolonging Na+ current through the channel. [15] The toxins are used in insecticides, vaccines, and protein engineering scaffolds. The toxins are now used to treat cancer patients by injecting fluorescent scorpion toxin into cancerous tissue to show tumor boundaries. Scorpion toxin genes are also used to kill insect pests by creating hypervirulent fungus in the insect through gene insertion.

Subfamilies

Related Research Articles

Tityustoxin is a toxin found in the venom of scorpions from the subfamily Tityinae. By binding to voltage-dependent sodium ion channels and potassium channels, they cause sialorrhea, lacrimation and rhinorrhea.

Birtoxin is a neurotoxin from the venom of the South African Spitting scorpion. By changing sodium channel activation, the toxin promotes spontaneous and repetitive firing much like pyrethroid insecticides do

Bestoxin is a neurotoxin from the venom of the South African spitting scorpion Parabuthus transvaalicus. Most likely, it targets sodium channel function, thus promoting spontaneous and repetitive neuronal firing. Following injection into mice, it causes non-lethal writhing behaviour.

BmKAEP is a neurotoxin from the venom of the Manchurian scorpion (Mesobuthus martensii). It is a β-toxin, which shift the activation voltage of sodium channels towards more negative potentials.

Ikitoxin is a neurotoxin from the venom of the South African Spitting scorpion that targets voltage-sensitive sodium channels. It causes unprovoked jumps in mice following intracerebroventricular injections.

Alpha-neurotoxin Group of neurotoxic peptides found in the venom of snakes

α-Neurotoxins are a group of neurotoxic peptides found in the venom of snakes in the families Elapidae and Hydrophiidae. They can cause paralysis, respiratory failure, and death. Members of the three-finger toxin protein family, they are antagonists of post-synaptic nicotinic acetylcholine receptors (nAChRs) in the neuromuscular synapse that bind competitively and irreversibly, preventing synaptic acetylcholine (ACh) from opening the ion channel. Over 100 α-neurotoxins have been identified and sequenced.

<i>delta</i>-Palutoxin

delta-Palutoxins (δ-palutoxins) consist of a homologous group of four insect-specific toxins from the venom of the spider Pireneitega luctuosa. They show a high toxicity against Spodoptera litura larvae by inhibiting sodium channels, leading to strong paralytic activity and eventually to the death of the insect.

BotIT2 is a neurotoxin from the scorpion Buthus occitanus tunetanus, which modifies activation and slows down the deactivation of voltage gated sodium channels.

Tamulotoxin is a venomous neurotoxin from the Indian Red Scorpion.

CgNa is a peptide toxin isolated from the sea anemone Condylactis gigantea. It causes an increased action potential duration by slowing down the inactivation of tetrodotoxin-sensitive sodium channels.

BotIT6 is a toxin that binds to insect voltage gated sodium channels. It decreases the amplitude of the action potential, leading to paralysis.

Centruroides suffusus suffusus toxin II (CssII) is a scorpion β-toxin from the venom of the scorpion Centruroides suffusus suffusus. CssII primarily affects voltage-gated sodium channels by causing a hyperpolarizing shift of voltage dependence, a reduction in peak transient current, and the occurrence of resurgent currents.

Spinoxin is a 34-residue peptide neurotoxin isolated from the venom of the Malaysian black scorpion Heterometrus spinifer. It is part of the α-KTx6 subfamily and exerts its effects by inhibiting voltage-gated potassium channels, specifically Kv1.2 and Kv1.3.

Pi4 is a short toxin from the scorpion Pandinus imperator that blocks specific potassium channels.

LmαTX3 is an α-scorpion toxin from Lychas mucronatus. that inhibits fast inactivation of voltage gated sodium-channels (VGSCs).

Beta-mammal toxin Cn2, also known as Cn2 toxin, is a single chain β-scorpion neurotoxic peptide and the primary toxin in the venom of the Centruroides noxius Hoffmann scorpion. The toxin specifically targets mammalian Nav1.6 voltage-gated sodium channels (VGSC).

LqhIT2 is a long-chain scorpion depressant β-toxin derived from Leiurus quinquestriatus hebraeus. It targets insect voltage-gated sodium channels (Navs) and shifts the voltage dependence of channel activation to a more negative membrane potential.

LmαTX5 is an α-scorpion toxin which inhibits the fast inactivation of voltage-gated sodium channels. It has been identified through transcriptome analysis of the venom gland of Lychas mucronatus, also known as the Chinese swimming scorpion – a scorpion species which is widely distributed in Southeast Asia.

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

Versutoxin

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

References

  1. ↑ PDB: 1PTX ​; Housset D, Habersetzer-Rochat C, Astier JP, Fontecilla-Camps JC (April 1994). "Crystal structure of toxin II from the scorpion Androctonus australis Hector refined at 1.3 A resolution". Journal of Molecular Biology. 238 (1): 88–103. doi:10.1006/jmbi.1994.1270. PMID   8145259.
  2. ↑ Krezel AM, Kasibhatla C, Hidalgo P, MacKinnon R, Wagner G (August 1995). "Solution structure of the potassium channel inhibitor agitoxin 2: caliper for probing channel geometry". Protein Science. 4 (8): 1478–89. doi:10.1002/pro.5560040805. PMC   2143198 . PMID   8520473.
  3. ↑ Miller C (July 1995). "The charybdotoxin family of K+ channel-blocking peptides". Neuron. 15 (1): 5–10. doi: 10.1016/0896-6273(95)90057-8 . PMID   7542463. S2CID   5256644.
  4. ↑ Osteen JD, Herzig V, Gilchrist J, Emrick JJ, Zhang C, Wang X, et al. (June 2016). "Selective spider toxins reveal a role for the Nav1.1 channel in mechanical pain". Nature. 534 (7608): 494–9. Bibcode:2016Natur.534..494O. doi:10.1038/nature17976. PMC   4919188 . PMID   27281198.
  5. ↑ Lin King JV, Emrick JJ, Kelly MJ, Herzig V, King GF, Medzihradszky KF, Julius D (September 2019). "A Cell-Penetrating Scorpion Toxin Enables Mode-Specific Modulation of TRPA1 and Pain". Cell. 178 (6): 1362–1374.e16. doi:10.1016/j.cell.2019.07.014. PMC   6731142 . PMID   31447178.
  6. ↑ Zhu L, Peigneur S, Gao B, Tytgat J, Zhu S (September 2013). "Two recombinant α-like scorpion toxins from Mesobuthus eupeus with differential affinity toward insect and mammalian Na(+) channels". Biochimie. 95 (9): 1732–40. doi:10.1016/j.biochi.2013.05.009. PMID   23743216.
  7. ↑ Bohlen CJ, Julius D (September 2012). "Receptor-targeting mechanisms of pain-causing toxins: How ow?". Toxicon. 60 (3): 254–64. doi:10.1016/j.toxicon.2012.04.336. PMC   3383939 . PMID   22538196.
  8. ↑ Kalia J, Milescu M, Salvatierra J, Wagner J, Klint JK, King GF, et al. (January 2015). "From foe to friend: using animal toxins to investigate ion channel function". Journal of Molecular Biology. 427 (1): 158–175. doi:10.1016/j.jmb.2014.07.027. PMC   4277912 . PMID   25088688.
  9. ↑ Ceciliani F, Bortolotti F, Menegatti E, Ronchi S, Ascenzi P, Palmieri S (April 1994). "Purification, inhibitory properties, amino acid sequence and identification of the reactive site of a new serine proteinase inhibitor from oil-rape (Brassica napus) seed". FEBS Letters. 342 (2): 221–4. doi:10.1016/0014-5793(94)80505-9. hdl: 2434/208504 . PMID   8143882. S2CID   42407931.
  10. ↑ Menegatti E, Tedeschi G, Ronchi S, Bortolotti F, Ascenzi P, Thomas RM, et al. (April 1992). "Purification, inhibitory properties and amino acid sequence of a new serine proteinase inhibitor from white mustard (Sinapis alba L.) seed". FEBS Letters. 301 (1): 10–4. doi: 10.1016/0014-5793(92)80199-Q . PMID   1451776.
  11. ↑ Rawlings ND, Tolle DP, Barrett AJ (March 2004). "Evolutionary families of peptidase inhibitors". The Biochemical Journal. 378 (Pt 3): 705–16. doi:10.1042/BJ20031825. PMC   1224039 . PMID   14705960.
  12. ↑ Kopeyan C, Mansuelle P, Sampieri F, Brando T, Bahraoui EM, Rochat H, Granier C (February 1990). "Primary structure of scorpion anti-insect toxins isolated from the venom of Leiurus quinquestriatus quinquestriatus". FEBS Letters. 261 (2): 423–6. doi:10.1016/0014-5793(90)80607-K. PMID   2311768. S2CID   40564285.
  13. ↑ Gregoire J, Rochat H (1983). "Covalent structure of toxins I and II from the scorpion Buthus occitanus tunetanus". Toxicon. 21 (1): 153–62. doi:10.1016/0041-0101(83)90058-2. PMID   6845379.
  14. ↑ Zhou XH, Yang D, Zhang JH, Liu CM, Lei KJ (January 1989). "Purification and N-terminal partial sequence of anti-epilepsy peptide from venom of the scorpion Buthus martensii Karsch". The Biochemical Journal. 257 (2): 509–17. doi:10.1042/bj2570509. PMC   1135608 . PMID   2930463.
  15. ↑ Rowe AH, Xiao Y, Scales J, Linse KD, Rowe MP, Cummins TR, et al. (2011) Isolation and Characterization of CvIV4: A Pain Inducing α- Scorpion Toxin. PLoS ONE 6(8): e23520. https://doi.org/10.1371/journal.pone.0023520
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