Halcurin

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Halcurin is a polypeptide neurotoxin from the sea anemone Halcurias sp. [1] Based on sequence homology to type 1 and type 2 sea anemone toxins it is thought to delay channel inactivation by binding to the extracellular site 3 on the voltage gated sodium channels in a membrane potential-dependent manner. [1]

Contents

Source and etymology

The polypeptide toxin halcurin is named after its source: the sea anemone genus Halcurias, [1] which are ocean dwelling solitary invertebrates. [2]

Chemistry

The amino acid sequence of halcurin is: VACRCESDGP DVRSATFTGT VDLWNCNTGW HKCIATYTAV ASCCKKD; it consists of 47 amino acids and has a molecular weight of 5,086 Da [1]

General information

A classification of sea anemone polypeptide neurotoxins has been proposed based on their amino acid sequence, dividing the group into three classes of sodium channel toxins. [3] Halcurin is structurally homologous with type 2 toxins, but also has sequence homology to type 1 toxins. [1] Type 1 and 2 toxins are composed of 46 to 49 amino acid residues, and cross-linked by three disulfide bridges. [2] Ten residues including six Cysteine (Cys) residues are completely conserved between type 1 and 2 toxins. [3] Therefore, it is possible that type 1 and 2 toxins have evolved from Halcurin as a common ancestor. [1]

Target

Type 1 and 2 toxins are known to target neurotoxin receptor site 3. [4] Based on the structural homology of halcurin with sea anemone toxin type 1 and 2 [1] it is likely to target neurotoxin receptor site 3. Neurotoxin receptor site 3 is predicted to be at the domain IV of voltage gated sodium channel, more specifically at the extracellular loop of segment 3-4. These voltage gated sodium channels are found in neurons, skeletal muscles, and cardiac muscles. [2]

Mode of action

The domain III and IV intracellular loop structure acts as a fast inactivation gate in voltage gated sodium channels. [5] Sea anemone toxin type 1 and 2 slow or prevent the conformational changes in domain IV segment 3-4 loop required for inactivation of the channel. [6] Based on the structural homology of halcurin to sea anemone neurotoxin type 1 and 2, [1] it is likely to have a similar mode of action.

Toxicity

Halcurin has a median lethal dose (LD50) of 5.8 μg/kg for crabs, but it does not show lethality in mice. [1]

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References

  1. 1 2 3 4 5 6 7 8 9 Ishida, M (Apr 1997). "Halcurin, a polypeptide toxin in the sea anemone Halcurias sp., with a structural resemblance to type 1 and 2 toxins". Toxicon. 35 (4): 537–544. doi:10.1016/s0041-0101(96)00143-2. PMID   9133708.
  2. 1 2 3 Bosmans, F (Dec 2002). "The sea anemone Bunodosoma granulifera contains surprisingly efficacious and potent insect-selective toxins". FEBS. 532 (1–2): 131–134. doi: 10.1016/s0014-5793(02)03653-0 . PMID   12459477.
  3. 1 2 Norton, RS (1991). "Structure and structure-function relationships of sea anemone proteins that interact with the sodium channel". Toxicon. 29 (9): 1051–1084. doi:10.1016/0041-0101(91)90205-6. PMID   1686683.
  4. ↑ Honma, Tomohiro; Shiomi, Kazuo (2006). "Peptide Toxins in Sea Anemones: Structural and Functional Aspects". Marine Biotechnology. 8 (1): 1–10. doi:10.1007/s10126-005-5093-2. PMC   4271777 . PMID   16372161.
  5. ↑ Caterall, WA (1995). "Structure and function of voltage-gated ion channels". Annual Review of Biochemistry. 64: 493–531. doi:10.1146/annurev.bi.64.070195.002425. PMID   7574491.
  6. ↑ Rogers, JC (Jul 1996). "Molecular determinants of high affinity binding of alpha-scorpion toxin and sea anemone toxin in the S3-S4 extracellular loop in domain IV of the Na+ channel alpha subunit". Journal of Biological Chemistry. 271 (27): 15950–15962. doi: 10.1074/jbc.271.27.15950 . PMID   8663157.
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