Versutoxin

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Delta Hexatoxin Hv1a
3D Model of 1vtx.png
3D stick model of delta-hexatoxin-Hv1 (versutoxin)
Identifiers
Symbolδ-HXTX-Hv1a
Pfam PF05353
InterPro IPR008017
OPM superfamily 112
OPM protein 1vtx
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Delta hexatoxin Hv1 (δ-HXTX-Hv1a, Versutoxin, or Versutotoxin, formerly known as Delta atracotoxin Hv1 and δ-ACTX-Hv1a) [1] is a neurotoxic component found in the venom of the Australian funnel web spider (Atrax robustus).

Contents

Delta hexatoxin Hv1 can result in fatality for primates, by downregulating the inactivation of voltage gated sodium ion channels (VGSCs) found in motor neurons.

The structure of versutoxin contains a central beta region with a cystine knot motif, commonly found in other neurotoxic polypeptides, but not found in sea anemone or alpha-scorpion toxins despite their similar effects in terms of sodium channel modulation. [2] [3]

Nomenclature

In 1997, Jamie I. Fletcher and his research associates introduced new nomenclature for classifying Australian funnel web spider toxins. They suggested replacing the trivial name 'versutoxin' with delta-hexatoxin-Hv1 instead. The delta represents the main biological activity of the neurotoxin; inhibiting sodium channels. [2]

In more recent research, atracotoxins have been rebranded as hexatoxins, but the two are still used interchangeably along with the abbreviations HXTX and ACTX. Delta and Hv1 are still used to specify the neurotoxic peptide versutoxin.

Structure

Delta hexatoxin Hv1 is a tightly folded polypeptide that contains a chain of 42 amino acid residues and has the chemical formula C206H318N58O60S9.  The amino acid sequence of delta hexatoxin Hv1 is:

CAKKRNWCGKTEDCCCPMKCVYAWYNEQGSCQSTISALWKKC [4] [5]

The tertiary structure of δ-ACTX-Hv1 contains a core β region that is made up of the residues Cys1Cys8, Cys14Val21, and Ser30Ser33, with Tyr22Gly29 protruding outwards. The β region has a three-stranded antiparallel β sheet comprising Asn6–Trp7 (β1), Met18–Val21 (β2), and Ser30–Ser33 (β3). The C-terminal end of the short β1 is held in place by a bifurcated hydrogen bond between the Cys8 amide proton and the carbonyl oxygens of the two residues preceding β strand 3 (Gln28 and Gly29). The β region also contains type II β turns at Lys3–Asn6 and Cys15–Met18 with a rare cis peptide bond at Cys16–Met 17. The nonpolar C-terminal 310 helix formed by Ile35Lys41, bordering Lys40 and Lys41 and connecting to β region with a disulphide bond next to a β turn. The β region contains hydrophobic cysteine sidechains bordered by a lysine sidechain.Three of the four disulphide bonds form the ICK. The structure of the cystine knot motif found in versutoxin is similar to the one found in gurmarin, a 35-residue plant polypeptide used to test the inhibition of sweet taste receptors. [2]

Uses

The peptides found in various venomous animals are capable of reducing inflammation, inactivating ion channels, and altering neurotransmitter production. Therefore, understanding the neurotoxins produced by these animals can potentially used as therapeutics for slowing down neurodegeneration. There are still many limitations in this research due to a lack of sufficient natural resources, however using recombinant DNA is used a way to mitigate this issue by promoting heterologous protein expression and peptide chemical synthesis. [6]

Mechanism behind Neurotoxic Properties

Versutoxin, in particular, is capable of affecting the voltage-gated sodium channels of prey. Studies conducted on primates show that δ-hexatoxin causes the neurotoxic effects by binding to VGSCs on neurons. δ-ACTX affects VGSCs similarly to α-scorpion and sea anemone toxins. Both of these types of toxins bind specifically to site 3 on the sodium channel. Despite versutoxin having a ICK which both α-scorpion and sea anemone toxins lack, researchers determined several other similarities in their anionic and cationic residue topography and confirmed that versutoxin also binds to site 3. They tested this by seeing how purified delta-ACTX-Hv1a affects the isolated cockroach (Periplaneta americana) dorsal unpaired median (DUM) neurons using a double sucrose-gap technique and comparing it to how it affected rat dorsal root ganglion (DRGs) neurons. They noted how delta-ACTX-Hv1a specifically affected voltage-gated Na+ channels of both specimens resulting in incomplete steady-state Na+ channel inactivation. [7]

Current Applications

Voltage gated sodium channels have been used as therapeutic targets in various modes of research, allowing versutoxin to also be used in the process. Some notable diseases versutoxin has been used as a potential therapeutic tool in include: Alzheimer's disease, Parkinson's disease, brain ischemia, glaucoma, and sclerosis. [6]

Versutoxin has also been used in biopesticide research. The structure of recombinant Nemertide α-1 (a neurotoxin found in carnivorous marine ribbon worms) was compared against recombinant delta-hexatoxin-Hv1 due to their similar VSGC targeting abilities. However, as of right now, not enough research has been done about the off target effects. [8]

See also

Related Research Articles

<span class="mw-page-title-main">Australian funnel-web spider</span> Family of mygalomorph spiders

Atracidae is a family of mygalomorph spiders, commonly known as Australian funnel-web spiders or atracids. It has been included as a subfamily of the Hexathelidae, but is now recognised as a separate family. All members of the family are native to Australia. Atracidae consists of three genera: Atrax, Hadronyche, and Illawarra, comprising 35 species. Some members of the family produce venom that is dangerous to humans, and bites by spiders of six of the species have caused severe injuries to victims. The bites of the Sydney funnel-web spider and northern tree-dwelling funnel-web spider are potentially deadly, but no fatalities have occurred since the introduction of modern first-aid techniques and antivenom.

<span class="mw-page-title-main">Poneratoxin</span> Paralyzing neurotoxic peptide

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. Specifically, poneratoxin acts on voltage gated sodium channels in skeletal muscle fibers, causing paralysis, and nociceptive fibers, causing pain. 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. It is additionally being studied for its uses in biological insecticides.

<span class="mw-page-title-main">Delta atracotoxin</span> Polypeptide found in the venom of the Sydney funnel-web spider

Delta atracotoxin is a low-molecular-weight neurotoxic polypeptide found in the venom of the Sydney funnel-web spider.

<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.

<span class="mw-page-title-main">Spider toxin</span> Family of toxins produced by spiders

Spider toxins are a family of proteins produced by spiders which function as neurotoxins. The mechanism of many spider toxins is through blockage of calcium channels.

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.

omega-Atracotoxin (ω-atracotoxin) is an insect-specific neurotoxin produced by the Blue Mountains funnel-web spider. Its phylogenetic specificity derives from its ability to antagonise insect, but not vertebrate, voltage-gated calcium channels. Two spatially proximal amino acid residues, Asn(27) and Arg(35), form a contiguous molecular surface that is essential for toxin activity. It has been proposed that this surface of the beta-hairpin is a key site for interaction of the toxin with insect calcium channels.

Raventoxins are neurotoxins from the venom of the spider Macrothele raveni.

Hainantoxins (HNTX) are neurotoxins from the venom of the Chinese bird spider Haplopelma hainanum. Hainantoxins specifically inhibit tetrodotoxin-sensitive Voltage-gated sodium channels, thereby causing blockage of neuromuscular transmission and paralysis. Currently, 13 different hainantoxins are known, but only HNTX-I, -II, -III, -IV and -V have been investigated in detail.

Huwentoxins (HWTX) are a group of neurotoxic peptides found in the venom of the Chinese bird spider Haplopelma schmidti. The species was formerly known as Haplopelma huwenum, Ornithoctonus huwena and Selenocosmia huwena. While structural similarity can be found among several of these toxins, HWTX as a group possess high functional diversity.

CSTX is a name given to a group of closely related neurotoxic peptides present in the venom of the wandering spider Cupiennius salei. There are twenty types so far described for this protein group. However, some are reclassified into cupiennins group of toxin, including CSTX-3, -4, -5, and -6, because of their chemical affinity. The first thirteen were isolated and identified in 1994 by Lucia Kuhn-Nentwig, Johann Schaller, and Wolfgang Nentwig of the Zoological Institute at the University of Bern, Switzerland. The different types are most likely the products of splicing variant of the same gene. They are all L-type calcium channel blockers, and also exhibit cytolytic activity by forming an alpha-helix across the cell membrane in mammalian neurons. They also inhibit voltage-gated calcium channels in insect neurons.

Atrax yorkmainorum is a venomous species of Australian funnel-web spider belonging to the Atracidae family and is found in forests in the vicinity of Canberra and south-eastern New South Wales. The genus Atrax was first documented in 1877 and the Atrax yorkmainorum species was first described in 2010.

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

ATX-II, also known as neurotoxin 2, Av2, Anemonia viridis toxin 2 or δ-AITX-Avd1c, is a neurotoxin derived from the venom of the sea anemone Anemonia sulcata. ATX-II slows down the inactivation of different voltage-gated sodium channels, including Nav1.1 and Nav1.2, thus prolonging action potentials.

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).

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

Syb-prII-1 is a β-type neurotoxin from the venom of the scorpion Olivierus martensii. It reduces the activity and the expression of the voltage-gated sodium channel Nav1.8.

U24-ctenitoxin-Pn1a is a neurotoxin that is naturally found in the venom of Latrodectus geometricus (L.geometricus). It reduces the inactivation of insect voltage-gated sodium channels. It is also thought to be a cysteine proteinase inhibitor.

Alpha-Insect Toxin LqhαIT is a neurotoxic protein found in the venom of the Leiurus hebraeus, commonly known as the Hebrew deathstalker scorpion. It is classified as an alpha-toxin due to its effect on insect voltage-gated sodium channels, causing prolonged neuronal firing that leads to paralysis in affected insects. This toxin has been widely studied for its unique interaction with insect nervous systems and has potential applications in neurophysiological research.

References

  1. Deuis, Jennifer R.; Mueller, Alexander; Israel, Mathilde R.; Vetter, Irina (2017-12-01). "The pharmacology of voltage-gated sodium channel activators". Neuropharmacology. Venom-derived Peptides as Pharmacological Tools. 127: 87–108. doi:10.1016/j.neuropharm.2017.04.014. ISSN   0028-3908. PMID   28416444. S2CID   46442872.
  2. 1 2 3 Fletcher JI, Chapman BE, Mackay JP, Howden ME, King GF (November 1997). "The structure of versutoxin (delta-atracotoxin-Hv1) provides insights into the binding of site 3 neurotoxins to the voltage-gated sodium channel". Structure. 5 (11): 1525–1535. doi: 10.1016/S0969-2126(97)00301-8 . PMID   9384567.
  3. Lüddecke T, Herzig V, von Reumont BM, Vilcinskas A (August 2021). "The biology and evolution of spider venoms". Biological Reviews of the Cambridge Philosophical Society. 97 (1): 163–178. doi: 10.1111/brv.12793 . PMID   34453398. S2CID   237342144.
  4. Brown MR, Sheumack DD, Tyler MI, Howden ME (March 1988). "Amino acid sequence of versutoxin, a lethal neurotoxin from the venom of the funnel-web spider Atrax versutus". The Biochemical Journal. 250 (2): 401–405. doi:10.1042/bj2500401. PMC   1148870 . PMID   3355530.
  5. "Amino acid sequence of versutoxin, a lethal neurotoxin from the venom of the funnel-web spider Atrax versutus". Biochemical Journal. 257 (3): 935. 1989-02-01. doi:10.1042/bj2570935a. ISSN   0264-6021. PMC   1135681 .
  6. 1 2 de Souza, Jessica M.; Goncalves, Bruno D. C.; Gomez, Marcus V.; Vieira, Luciene B.; Ribeiro, Fabiola M. (2018). "Animal Toxins as Therapeutic Tools to Treat Neurodegenerative Diseases". Frontiers in Pharmacology. 9: 145. doi: 10.3389/fphar.2018.00145 . ISSN   1663-9812. PMC   5829052 . PMID   29527170.
  7. Grolleau, F.; Stankiewicz, M.; Birinyi-Strachan, L.; Wang, X.H.; Nicholson, G.M.; Pelhate, M.; Lapied, B. (2001-02-15). "Electrophysiological analysis of the neurotoxic action of a funnel-web spider toxin, delta-atracotoxin-HV1a, on insect voltage-gated Na+ channels". Journal of Experimental Biology. 204 (4): 711–721. Bibcode:2001JExpB.204..711G. doi:10.1242/jeb.204.4.711. hdl: 10453/5728 . ISSN   0022-0949. PMID   11171353.
  8. Bell, Jack; Sukiran, Nur Afiqah; Walsh, Stephen; Fitches, Elaine C. (2021-07-15). "The insecticidal activity of recombinant nemertide toxin α-1 from Lineus longissimus towards pests and beneficial species". Toxicon. 197: 79–86. Bibcode:2021Txcn..197...79B. doi:10.1016/j.toxicon.2021.04.003. ISSN   0041-0101. PMID   33852905. S2CID   233244240.