APEKTx1

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APEKTx1
Identifiers
SymbolN/A
RefSeq P86862.1
UniProt P86862
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Structures Swiss-model
Domains InterPro

Kunitz-type serine protease inhibitor APEKTx1 is a peptide toxin derived from the sea anemone Anthopleura elegantissima. This toxin has a dual function, acting both as a serine protease inhibitor and as a selective and potent pore blocker of Kv1.1, a shaker related voltage-gated potassium channel.

Contents

Sources

APEKTx1 is a potent toxin purified from the sea anemone A. elegantissima. [1] Besides APEKTx1, other toxins such as APETx1, [2] APE1-1, APE1-2, APE2-2, ApC, [3] and APETx2 [4] have been identified in A. elegantissima.

Chemistry

APEKTx1 monomer structure prediction (Alpha-fold model). The average per residue confidence (pLDDT) is 91.46%. The levels of confidence of the model are color coded: dark blue very high (pLDDT > 90), light blue high (90 > pLDDT > 70), orange low (70 > pLDDT > 50), and yellow very low (pLDDT < 50). APEKTx1 monomer structure prediction (Alpha-fold model).gif
APEKTx1 monomer structure prediction (Alpha-fold model).The average per residue confidence (pLDDT) is 91.46%. The levels of confidence of the model are color coded: dark blue very high (pLDDT > 90), light blue high (90 > pLDDT > 70), orange low (70 > pLDDT > 50), and yellow very low (pLDDT < 50).

This peptide has 65 amino acids crosslinked by 3 disulphide bridges, and has a molecular mass of 7475 Da. It acts as a monomer. The toxin belongs to the type 2 sea anemone peptides targeting voltage-gated K channels. Other type 2 toxins are the kalicludines from Anemonia sulcata , which selectively block Kv1.2 channels, [5] and SHTX II from Stichodactyla haddoni . [6] Structural homology is also shared with the basic pancreatic trypsin inhibitor (BPTI), a very potent Kunitz-type protease inhibitor, and dendrotoxins (DTX I and α-DTX), which are potent inhibitors of voltage-gated potassium channels. [1]

APEKTx1
Amino acid sequence
INSICLLPKKQGFCRARFPRFYYNSSTRRCEMFY

YGGCGGNANNFNTLEECEKVCLGYGEAWKAP

Target

APEKTx1 is a highly selective blocker of the voltage-gated potassium channel Kv1.1 with no effect on other tested potassium channels (Kv1.2, Kv1.3, Kv1.4, Kv1.5, Kv1.6, Shaker IR, Kv2.1, Kv3.1, Kv4.2 and Kv4.3). [1] APEKTx1 selectively blocks Kv1.1 channels with an IC50 value of 0.9 nM, which makes it between a 700 to 3000 times more potent inhibitor than the two known sea anemone peptides targeted against Kv channels (kalicludines and SHTX II). [1] APEKTx1 is thought to interact with Kv1.1 through the aliphatic residue alanine (A352), an acidic residue glutamate (E353), and an aromatic residue tyrosine (Y379), as a mutation in these sites causes a loss in affinity of the toxin for Kv1.1. [1] [7] These residues are located in the H5-loop between the S5 and S6 domains and are part of the channel’s pore. [7] [8]

In addition, APEKTx1 acts as a potent trypsin inhibitor (Kd= 124 nM), probably a competitive one. However, trypsin inhibition is more potent (as it has a higher affinity) in BPTI, which can be explained by the presence of Phe13 and Pro19 in APEKTx1, causing an unfavorable interaction. [1]

Mode of action

APEKTx1 works by blocking the Kv1.1 channel in its open conformation, showing no effect on the voltage-dependence of channel gating. [1] In contrast to certain homologous toxins like DTX-K, APEKTx1 can completely block the K+ current. The binding site of the toxin is presumed to be located at the extracellular side, as evidenced by the rapid inhibition of current through Kv1.1 channels and the reversible binding upon washout. Unlike the irreversible binding of DTX K dendrotoxins (which are homologous to APEKTx1), APEKTx1's action is reversible. This is possibly due to the substitution of a lysine (either Lys3 or Lys26) with a neutral arginine in APEKTx1. [1] APEKTx1 likely contains a dyad: a pair of amino acid residues composed of a basic residue and a hydrophobic residue separated from each other by 6.6 ± 1.0 Å that interacts with the aromatic residues on the P-loop participating in the channel-toxin interaction affinity. [1] [9] APEKTx1’s dyad is formed by Arg15 and Phe13, separated by 6.2 Å, contributing to the formation of a physical barrier that opposes the K+ efflux. [10] Presumably, the side chain of Arg15 enters the Kv1.1 pore and interacts with the Asp377 residues, while Phe13 interacts with hydrophobic residues, including Tyr375, which is critically involved in the interaction affinity with the sea anemones toxins. [1] [11]

The interaction of APEKTx1 with Kv1.1 channels follows the kinetic behavior of a bimolecular reaction, meaning that the rate of binding depends on the concentration of both reactants (toxin and channel). [1]

Related Research Articles

<span class="mw-page-title-main">Dendrotoxin</span> Chemical compound

Dendrotoxins are a class of presynaptic neurotoxins produced by mamba snakes (Dendroaspis) that block particular subtypes of voltage-gated potassium channels in neurons, thereby enhancing the release of acetylcholine at neuromuscular junctions. Because of their high potency and selectivity for potassium channels, dendrotoxins have proven to be extremely useful as pharmacological tools for studying the structure and function of these ion channel proteins.

Calcicludine (CaC) is a protein toxin from the venom of the green mamba that inhibits high-voltage-activated calcium channels, especially L-type calcium channels.

<span class="mw-page-title-main">KCNA3</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">Stichodactyla toxin</span> Protein family

Stichodactyla toxin is a 35-residue basic peptide from the sea anemone Stichodactyla helianthus that blocks a number of potassium channels. Related peptides form a conserved family of protein domains known as the ShkT domain. Another well-studied toxin of the family is BgK from Bunodosoma granulifera.

Parabutoxin (PBTx) is a Shaker-related voltage-gated K+ channel (Kvα1) inhibitor purified from different Parabuthus scorpion species found in southern Africa. It occurs in different forms: parabutoxin 1 (PBTx1), parabutoxin 2 (PBTx2), parabutoxin 3 (PBTx3) and parabutoxin (PBTx10). The different variants have different affinities towards Kvα1 channels.

<span class="mw-page-title-main">Pandinus imperator (Pi3) toxin</span>

Pi3 toxin is a purified peptide derivative of the Pandinus imperator scorpion venom. It is a potent blocker of voltage-gated potassium channel, Kv1.3 and is closely related to another peptide found in the venom, Pi2.

BgK is a neurotoxin found within secretions of the sea anemone Bunodosomagranulifera which blocks voltage-gated potassium channels, thus inhibiting neuronal repolarization.

Kaliseptine (AsKS) is a neurotoxin which can be found in the snakelocks anemone Anemonia viridis. It belongs to a class of sea anemone neurotoxins that inhibits voltage-gated potassium channels.

HsTx1 is a toxin from the venom of the scorpion Heterometrus spinifer. HsTx1 is a very potent inhibitor of the rat Kv1.3 voltage-gated potassium channel.

HgeTx1 (systematic name: α-KTx 6.14) is a toxin produced by the Mexican scorpion Hoffmanihadrurus gertschi that is a reversible blocker of the Shaker B K+-channel, a type of voltage-gated potassium channels.

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

SHTX is a toxin derived from the sea anemone Stichodactyla haddoni; there are four different subtypes, SHTX I, II, III and IV. SHTX I, II and III can paralyze crabs by acting on potassium channels, while SHTX IV works on sodium channels, and is lethal to crabs.

Kalicludine (AsKC) is a blocker of the voltage-dependent potassium channel Kv1.2 found in the snakeslocks anemone Anemonia viridis, which it uses to paralyse prey.

APETx1 is a peptide toxin from the venom of the sea anemone Anthopleura elegantissima. The toxin acts as a gating modifier on the human ether-à-go-go-related gene (hERG) channel, a type of voltage-gated potassium channel, and as a blocker of voltage-gated sodium channels, including Nav1.2 and Nav1.8.

BmP02, also known as α-KTx 9.1 or Bmkk(6), is a toxin from the Buthus Martensi Karsch (BmK) scorpion. The toxin acts on potassium channels, blocking Kv1.3 and slowing the deactivation of Kv4.2. BmP02 is not toxic to humans or mice.

<span class="mw-page-title-main">BscTx3</span>

BcsTx3, also known as Kappa-actitoxin-Bsc4a, is a neurotoxin that blocks voltage-gated potassium channel (Kv1/KCNA). It is purified from the venom of Bunodosoma caissarum.

AsKC11 is a toxin found in the venom of the sea anemone, Anemonia sulcata. This toxin is part of the Kunitz peptide family and has been shown to be an activator of G protein-coupled inwardly-rectifying potassium (GIRK) channels 1/2, involved in the regulation of cellular excitability. 

Toxin BF9 is a Kunitz-type peptide, coming from snakes, with a dual functionality. The toxin is able to inhibit both serine proteases and potassium channels.

<span class="mw-page-title-main">LmKTT-1a</span> Scorpion Toxin

LmKTT-1a is a bifunctional Kunitz-type toxin belonging to the ẟ-KTx subfamily, which can be found in the venom of Lychasmucronatus. As a bifunctional toxin, it both inhibits trypsin activity and blocks Kv1 channels with a weak selectivity towards Kv1.3 channels.

κ-KTx2.5 is a toxin found in the venom of the scorpion, Opisthacanthuscayaporum. The toxin belongs to the κ-KTx family, a channel blocker family that targets voltage-gated potassium channels (Kv) 1.1 and 1.4.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 Peigneur S, Billen B, Derua R, Waelkens E, Debaveye S, Béress L, Tytgat J (July 2011). "A bifunctional sea anemone peptide with Kunitz type protease and potassium channel inhibiting properties". Biochemical Pharmacology. 82 (1): 81–90. doi:10.1016/j.bcp.2011.03.023. PMID   21477583. S2CID   20886727.
  2. ↑ Diochot S, Loret E, Bruhn T, Béress L, Lazdunski M (July 2003). "APETx1, a new toxin from the sea anemone Anthopleura elegantissima, blocks voltage-gated human ether-a-go-go-related gene potassium channels". Molecular Pharmacology. 64 (1): 59–69. doi:10.1124/mol.64.1.59. PMID   12815161.
  3. ↑ Bruhn T, Schaller C, Schulze C, Sanchez-Rodriguez J, Dannmeier C, Ravens U, et al. (May 2001). "Isolation and characterisation of five neurotoxic and cardiotoxic polypeptides from the sea anemone Anthopleura elegantissima". Toxicon. 39 (5): 693–702. doi:10.1016/s0041-0101(00)00199-9. PMID   11072049.
  4. ↑ Diochot S, Baron A, Rash LD, Deval E, Escoubas P, Scarzello S, et al. (April 2004). "A new sea anemone peptide, APETx2, inhibits ASIC3, a major acid-sensitive channel in sensory neurons". The EMBO Journal. 23 (7): 1516–1525. doi:10.1038/sj.emboj.7600177. PMC   391081 . PMID   15044953.
  5. ↑ Schweitz H, Bruhn T, Guillemare E, Moinier D, Lancelin JM, Béress L, Lazdunski M (October 1995). "Kalicludines and kaliseptine. Two different classes of sea anemone toxins for voltage sensitive K+ channels". The Journal of Biological Chemistry. 270 (42): 25121–25126. doi: 10.1074/jbc.270.42.25121 . PMID   7559645.
  6. ↑ Honma T, Kawahata S, Ishida M, Nagai H, Nagashima Y, Shiomi K (April 2008). "Novel peptide toxins from the sea anemone Stichodactyla haddoni". Peptides. 29 (4): 536–544. doi:10.1016/j.peptides.2007.12.010. PMID   18243416. S2CID   207356560.
  7. 1 2 Hurst RS, Busch AE, Kavanaugh MP, Osborne PB, North RA, Adelman JP (October 1991). "Identification of amino acid residues involved in dendrotoxin block of rat voltage-dependent potassium channels". Molecular Pharmacology. 40 (4): 572–576. PMID   1921987.
  8. ↑ Tytgat J, Debont T, Carmeliet E, Daenens P (October 1995). "The alpha-dendrotoxin footprint on a mammalian potassium channel". The Journal of Biological Chemistry. 270 (42): 24776–24781. doi: 10.1074/jbc.270.42.24776 . PMID   7559595.
  9. ↑ Dauplais M, Lecoq A, Song J, Cotton J, Jamin N, Gilquin B, et al. (February 1997). "On the convergent evolution of animal toxins. Conservation of a diad of functional residues in potassium channel-blocking toxins with unrelated structures". The Journal of Biological Chemistry. 272 (7): 4302–4309. doi: 10.1074/jbc.272.7.4302 . PMID   9020148.
  10. ↑ Mouhat S, De Waard M, Sabatier JM (February 2005). "Contribution of the functional dyad of animal toxins acting on voltage-gated Kv1-type channels". Journal of Peptide Science. 11 (2): 65–68. doi:10.1002/psc.630. PMID   15635666. S2CID   31444823.
  11. ↑ Gilquin B, Braud S, Eriksson MA, Roux B, Bailey TD, Priest BT, et al. (July 2005). "A variable residue in the pore of Kv1 channels is critical for the high affinity of blockers from sea anemones and scorpions". The Journal of Biological Chemistry. 280 (29): 27093–27102. doi: 10.1074/jbc.M413626200 . PMID   15890656.
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