Chemistry:RTX-III

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RTX-III (neurotoxin-III,δ-SHTX-Hcr1a) is a neurotoxin peptide derived from the Sebae anemone Radianthus crispa. The toxin targets voltage-dependent sodium channels by preventing its complete inactivation, which can lead to a prolonged influx of sodium ions and depolarization of the cell's membrane.

RTX-III is secreted by the sea anemone Radianthus crispa, also known as Heteractis crispa or Radianthus macrodactylus, which inhabits the Indian and Pacific Oceans.[1]

Structure

Primary structure

The RTX-III neuropeptide consists of 48 amino acids cross-linked by three disulfide bridges.[2]

The amino acid sequence of the neurotoxin-III is:

[2]

and its molecular mass is 5378.33 Da.[2]

3D-model of the structure of RTX-III[3]

Secondary structure

Due to RTX-III's structural characteristics, this toxin is categorized as a type II sea anemone neurotoxin. The toxin has a guanidine group of Arg13 residues,[1] as well as disulfide bridges, which may be important in maintaining its active conformation.[4]

Homology

RTX-III is highly homologous with ShI, also a type II toxin, from the sea anemone Stichodactyla helianthus, whose sequence is 88% identical.[2][5][6] RTX-III also shares significant homology with other toxins in the type II family, including RpII and RTX-VI.[7]

Target

RTX-III is a Nav activator (also known as a sodium channel opener), which elicits changes in the functioning voltage-gated sodium channels of arthropods, insects and mammals. Research has shown evidence of affinity binding with various types of sodium channels.[7] The toxin modulates the BgNav1 subtype of insects and the VdNav1 subtype of arachnoids. In mammals, it selectively modulates Nav 1.3 and Nav1.6 sodium channels.[7]

All sea anemone toxins are thought to bind within binding site 3 of voltage-dependent sodium channels. The binding site for RTX-III, in particular, is proposed to overlap with that of the channel-inactivating scorpion α-toxins and spider δ-toxins, though it is not entirely identical.[7]

Mode of action

RTX-III prevents or reduces the speed with which sodium channels are inactivated. The toxin inhibits the inactivation of the voltage-dependent sodium channels in a selective manner. The sodium channels may stay open for longer than normal, and consequently, the influx of sodium is prolonged.[1] In turn, the influx of sodium may depolarize the membrane potential value towards a more positive membrane potential. Therefore, inactivation will be incomplete and less sensitive to any potential changes, slowing down the kinetics of sodium inactivation.[7]

RTX-III differs from the conventional way in which sea anemones operate – an arginine residue being the center of binding with a sodium channel.[1] In the case of neurotoxin-III, it is hypothesized that Arg13 may play a role in selecting specific sodium channel isoforms.[1][8][9] However, these findings might only partially apply to RTX-III since a different, homologous toxin was investigated – RTX-VI.[8][9]

Toxicity and potency

RTX-III presents a high toxicity in mammals. The LD50 for mice varies from 25 to 40 μg/kg, while the LD100 is 82 μg/kg in arthropods.[2] Specific amino acid substitutions in the RTX-III sequence occur at the positions most toxic for mice.[2]

The EC50 values of RTX-III also differ between mammals (381.8 nM) and insects/arthropods (978.1 nM).[7] RTX-III displays a lower potency in arachnid and insect channels, with relatively high EC50 values. However, in mammalian channels the toxin may be more potent, showing smaller EC50 values.[7] Since RTX-III is produced by a sea anemone, its main role is the effective modulation of arthropod sodium channels, so that the prey is immobilized but not necessarily killed.[7]

Table 1. LD50,[2] LD100[2] and EC50[7] values of the Heteractis neurotoxin RTX-III
LD50 (μg/kg) LD100(μg/kg) EC50 (nM)
Mammals 25-40 x 381.8
Insects / Arthropods x 82 978.1

RTX-III's toxic properties are distributed between its many functional groups, such as the Arg-13 guanidine group[10] and the Gly-1 amino group.[1]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Mahnir, Vladimir M.; Kozlovskaya, Emma P. (1991-01-01). "Structure-toxicity relationships of neurotoxin RTX-III from the sea anemone Radianthus macrodactylus: Modification of amino groups". Toxicon 29 (7): 819–826. doi:10.1016/0041-0101(91)90218-G. ISSN 0041-0101. PMID 1681602. Bibcode: 1991Txcn...29..819M. https://linkinghub.elsevier.com/retrieve/pii/004101019190218G. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 Zykova, Tatiana A.; Vinokurov, Leonid M.; Kozlovskaya, Emma P.; Elyakov, Georgy B. (1985). "Amino acid sequence of neurotoxin III from the sea anemone Radianthus macrodactylus". Bioorganicheskaya Khimiya 11: 302–310. 
  3. ↑ Monastyrnaya, Margarita Mikhailovna; Kalina, Rimma Sergeevna; Kozlovskaya, Emma Pavlovna (2023). "The Sea Anemone Neurotoxins Modulating Sodium Channels: An Insight at Structure and Functional Activity after Four Decades of Investigation" (in en). Toxins 15 (1): 8. doi:10.3390/toxins15010008. ISSN 2072-6651. PMID 36668828. 
  4. ↑ Nabiullin, A. A.; Odinokov, Stanislav E.; Vozhova, E. I.; Kozlovskaya, Emma. P.; Elyakov, Georgy B. (1982). "A circular-dichroism study on the conformational stability of toxin-I from sea anemone Radianthus macrodactylus". Bioorganicheskaya Khimiya 8 (12): 1644–1648. 
  5. ↑ Kem, William R.; Parten, Benne; Pennington, Michael W.; Price, David A.; Dunn, Ben M. (1989-04-18). "Isolation, characterization, and amino acid sequence of a polypeptide neurotoxin occurring in the sea anemone Stichodactyla helianthus" (in en). Biochemistry 28 (8): 3483–3489. doi:10.1021/bi00434a050. ISSN 0006-2960. PMID 2568126. https://pubs.acs.org/doi/abs/10.1021/bi00434a050. 
  6. ↑ Wilcox, G R; Fogh, R H; Norton, R S (1993). "Refined structure in solution of the sea anemone neurotoxin ShI.". Journal of Biological Chemistry 268 (33): 24707–24719. doi:10.1016/s0021-9258(19)74523-2. ISSN 0021-9258. PMID 7901218. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 Kalina, Rimma S.; Peigneur, Steve; Zelepuga, Elena A.; Dmitrenok, Pavel S.; Kvetkina, Aleksandra N.; Kim, Natalia Y.; Leychenko, Elena V.; Tytgat, Jan et al. (2020). "New Insights into the Type II Toxins from the Sea Anemone Heteractis crispa" (in en). Toxins 12 (1): 44. doi:10.3390/toxins12010044. ISSN 2072-6651. PMID 31936885. 
  8. ↑ 8.0 8.1 Moran, Yehu; Cohen, Lior; Kahn, Roy; Karbat, Izhar; Gordon, Dalia; Gurevitz, Michael (2006-07-01). "Expression and Mutagenesis of the Sea Anemone Toxin Av2 Reveals Key Amino Acid Residues Important for Activity on Voltage-Gated Sodium Channels" (in en). Biochemistry 45 (29): 8864–8873. doi:10.1021/bi060386b. ISSN 0006-2960. PMID 16846229. https://pubs.acs.org/doi/10.1021/bi060386b. 
  9. ↑ 9.0 9.1 Honma, Tomohiro; Shiomi, Kazuo (2006-01-01). "Peptide Toxins in Sea Anemones: Structural and Functional Aspects" (in en). Marine Biotechnology 8 (1): 1–10. doi:10.1007/s10126-005-5093-2. ISSN 1436-2236. PMID 16372161. Bibcode: 2006MarBt...8....1H. 
  10. ↑ Mahnir, Vladimir M.; Kozlovskaya, Emma P.; Elyakov, Georgy B. (1989-01-01). "Modification of arginine in sea anemone toxin RTX-III from Radianthus macrodactylus". Toxicon 27 (10): 1075–1084. doi:10.1016/0041-0101(89)90001-9. ISSN 0041-0101. PMID 2573177. Bibcode: 1989Txcn...27.1075M. https://linkinghub.elsevier.com/retrieve/pii/0041010189900019. 



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