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
PfamPF05353
InterProIPR008017
OPM superfamily112
OPM protein1vtx

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).

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 animo acid residues and has the chemical formula C206H318N58O60S9.  The animo acid sequence of delta hexatoxin Hv1 is:

C A K K R N W C G K T E D C C C P M K C V Y A W Y N E Q G S C Q S T I S A L W K K C[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 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

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. ^ a b c 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: 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. ^ a b 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. doi:10.1242/jeb.204.4.711. 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. doi:10.1016/j.toxicon.2021.04.003. ISSN 0041-0101. PMID 33852905. S2CID 233244240.