Delta hexatoxin Hv1 (''δ''-HXTX-Hv1a, Versutoxin, or Versutotoxin, formerly known as Delta atracotoxin Hv1 and ''δ''-ACTX-Hv1a) is a
neurotoxic
Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specifical ...
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
neuron
A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
s.
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
Sea anemones ( ) are a group of predation, predatory marine invertebrates constituting the order (biology), order Actiniaria. Because of their colourful appearance, they are named after the ''Anemone'', a terrestrial flowering plant. Sea anemone ...
or
alpha-scorpion toxins despite their similar effects in terms of
sodium channel modulation.
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
In pharmacology, biological activity or pharmacological activity describes the beneficial or adverse effects of a drug on living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient or ...
of the neurotoxin;
inhibiting sodium channels.
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
Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty ...
that contains a chain of 42 amino acid residues and has the chemical formula C
206H
318N
58O
60S
9. The amino acid sequence of delta hexatoxin Hv1 is:The tertiary structure of ''δ''-ACTX-Hv1 contains a core ''β'' region that is made up of the residues
Cys1–
Cys8,
Cys14–
Val21, and
Ser30–
Ser33, with
Tyr22–
Gly29 protruding outwards. The ''β'' region has a three-stranded
antiparallel ''β'' sheet comprising
Asn6–Trp7 (''β''1),
Met18–Val21 (''β''2), and Ser30–Ser33 (''β''3). The C-terminal end of the short ''β''1 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
Ile35–
Lys41, 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.
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
Recombinant DNA (rDNA) molecules are DNA molecules formed by laboratory methods of genetic recombination (such as molecular cloning) that bring together genetic material from multiple sources, creating sequences that would not otherwise be fo ...
is used a way to mitigate this issue by promoting ''heterologous protein expression'' and ''peptide chemical synthesis''.
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.
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.
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.
See also
*
Atracotoxin Atracotoxin may refer to:
* δ-Atracotoxin ( robustoxin or versutoxin)
* ω-Atracotoxin
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