HsTx1 is a toxin from the venom of the scorpion ''

Heterometrus spinifer ''Heterometrus spinifer'', the Asian forest scorpion, giant blue scorpion, or giant forest scorpion, is a species of scorpions belonging to the family Scorpionidae. Description ''H. spinifer'' can reach a length around . The body is shiny blac ...

''. HsTx1 is a very potent inhibitor of the rat

Kv1.3 Potassium voltage-gated channel, shaker-related subfamily, member 3, also known as KCNA3 or Kv1.3, is a protein that in humans is encoded by the ''KCNA3'' gene. Potassium channels represent the most complex class of voltage-gated ion channels from ...

voltage-gated potassium channel Voltage-gated potassium channels (VGKCs) are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a crucial role in returning the depolarized ce ...

Etymology

HsTx1 stands for ''

'' Toxin 1. The systematic name for this toxin is α-KTx 6.3.https://www.uniprot.org/docs/scorpktx.txt

Sources

HsTx1 is produced by ''

'', also known as Asia Giant Forest Scorpion or Malaysian Black Scorpion. *Taxon Identifier: 118530

Structure

HsTx1 is characterized by a single polypeptide chain of 34 amino acid residues containing 8 Cysteine residues and an amidated C-Terminal end. Its core has a hydrophobic structure and the backbone displays one

α-helix The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues e ...

and two

β-sheets The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gen ...

regions that connect the N-terminal and the C-terminal ends. The entire structure is cross-linked by 4 disulfide bridges. Scorpion toxins characterized that block voltage-gated potassium channels, have a highly conserved triplet of amino acids in the positions 23, 25 and 26 that is believed to have a role in the affinity for the channels. There are also two highly conserved amino acid residues (one positively charged and the other an aromatic residue) considered critical for the binding to specific α-subunits of the potassium channel depending on their position in the sequence. HsTx1 has the triplet in its sequence but does not show homology in the doublet sequence, hinting that it might be able to bind to different subunits in the channel.

Homology and categories

Scorpion venom usually contains different toxins that could influence the physiological functioning of

nervous system In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes th ...

binding the sites and blocking the activity of

voltage-gated ion channels Voltage-gated ion channels are a class of transmembrane proteins that form ion channels that are activated by changes in the electrical membrane potential near the channel. The membrane potential alters the conformation of the channel proteins, ...

. The main targets of these toxins are potassium channels and

sodium channels Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the channel ...

. On the basis of their amino acid sequences comparison those toxins are classified in 4 groups(3). HsTx1 Toxin belongs to the fourth group, which also contains toxins Pi1, Pi2 and Pi3 (from ''Pandinus imperator'' scorpion) and

Maurotoxin Maurotoxin (abbreviated MTX) is a peptide toxin from the venom of the Tunisian chactoid scorpion '' Scorpio maurus palmatus'', from which it was first isolated and from which the chemical gets its name. It acts by blocking several types of volt ...

(MTX, from ''

Scorpio maurus ''Scorpio maurus'' is a species of North African and Middle Eastern scorpion, also known as the large-clawed scorpion or Israeli gold scorpion and lesser known as Zerachia scorpion. This is a small/medium-sized scorpion from the family Scorpion ...

'' scorpion). Main structural characteristics are the presence of 34 amino acid residues and 3 or 4 Disulfide bridges. Toxins of the fourth group have 50%-70% sequence identity overlap with each other. In general the sequence of HsTx1 has only the 32-47% affinity with that of the toxins belonging to the three disulfide bridges group. Despite that their 3D backbone structures are similar. Within the 4 bridge groups, there is more structural homology between Pi1 and MTX than with HsTx1, since HsTx1 does not share the same position of cysteine residues responsible for the sulfide bonds in its sequence. These differences in homology could explain the differences in pharmacological activity such as HsTx1 binding with more affinity and specificity to the Kv1.3.

Target and mode of action

HsTx1 is one of the most effective peptidic inhibitors of Kv1.3 channels with an IC50 of 12 pM. Unlike other toxins from the same family HsTx1 does not seem to affect the

apamin Apamin is an 18 amino acid globular peptide neurotoxin found in apitoxin ( bee venom). Dry bee venom consists of 2–3% of apamin. Apamin selectively blocks SK channels, a type of Ca2+-activated K+ channel expressed in the central nervous syste ...

-sensitive calcium-dependent potassium channel. The affinity and interaction with the potassium channel is thought to depend both on the amino acid sequence of the toxin and the modification of its C-terminal end. It has been found that the amidated form might have a role in the higher affinity for the potassium channel. Positively charged residues of the toxin interact with negatively charged residues in the channel by electrostatic and Van der Waals forces. The toxin induces a reversible blocking effect by the formation of two salt bridges and six

hydrogen bonds In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a ...

in the mouth of the pore of the channel. The five critical residues thought to interact with the channel are Y26, K29, M31, N32, R39.

Research

Because peptide toxins usually have high affinity for their targets, the small dosage needed to see effects makes them good candidates for therapies that aim to specifically and efficiently block

. The aim now is to overcome the affinity range that usually involves more than one type of channel so that the effects can be specifically targeted and there are no side-effects. Kv1.3 channels are up-regulated in activated T effector memory cells in humans. Study of Kv1.3 blockers such as HsTx1 could lead to new treatments to autoimmune disorders such as

multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...

and

type 1 diabetes Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for ...

References

{{Potassium channel blockers Protein toxins Neurotoxins Ion channel toxins Scorpion toxins