OSK3

OSK3, from the venom of the scorpion Orthochirus scrobiculosus, is a potassium channel blocker that belongs to the α-KTx8 subfamily and targets the voltage-gated potassium channels KCNA2 (K_v1.2), and KCNA3 (K_v1.3).

OSK3
Identifiers
The protein structure of OSK3
Superfamily: Short scorpion toxin
Family: Potassium channel inhibitor
Subfamily: Alpha-KTx 08
Uniprot: A0A1L2FZD4
Species: Orthochirus scrobiculosus

Etymology and source

OSK3 is secreted from the venom gland of Orthochirus scrobiculosus, which is also known as the Central Asian scorpion and belongs to the Buthoidea superfamily, the largest scorpion superfamily.^[1] The toxin gets its name from the acronym of the species it originates from, the type of ion channel it blocks, and the order of its discovery within the toxin family.

Chemistry

Structure

The propeptide of OSK3 is a small polypeptide consisting of 57 amino acids, with a mean molecular mass of 6386 Da. It is then further spliced into a mature form consisting of 29 amino acid residues, among which 6 are cysteine residues that make up 3 intracellular disulfide bonds. The mean mass of the OSK3 toxin is 3206.3 ± 0.2 Da.^[1]^[2]

Sequence of OSK3 propeptide:^[3]

MCRLYAIILI VLVMNVIMTI IPDSKVEVVS CEDCPEHCST QKARAKCDND KCVCEPI

Family

OSK3 (α-KTx 8.8) belongs to the α-KTx family, which is a scorpion venom toxin family blocking potassium channels. It is the most abundant and shows the highest diversity among the six KTx families (α-,β-,γ-,δ-,κ-, and λ-KTx).^[4] Additionally, OSK3 is the eighth member of the α-KTx8 subfamily. The preceding members are AmP01 (α-KTx 8.1), BmP01 (α-KTx 8.2), LpII (α-KTx 8.3), LPIII (α-KTx 8.4), OdK1 (α-KTx 8.5), MeuKTx-1 (α-KTx 8.6), and MeKTx1-2 (α-KTx 8.7).^[2]

Homology

All members of the α-KTx8 subfamily consist of 29 amino acid residues. 97% of the residues in OSK3 are identical with AmP01 (α-KTx8.1) which originates from the scorpion Androctonus mauretanicus mauretanicus, with only one differing amino acid residue. OSK3 differs from OdK1, α-KTx8.5, with only two C-terminal residues. Due to this structural difference, specific interactions of the residues with the type of voltage gated potassium channels also vary; OdK1 targets K_v1.2 whereas OSK3 inhibits both K_v1.2 and K_v1.3 channels.^[2]

Target

OSK3 displays a novel selectivity profile as compared to the rest of the α-KTx8 subfamily, targeting selectively the voltage-gated potassium channels K_v1.2 and K_v1.3. At 1 μM, it blocks K_v1.2 channels completely and K_v1.3 channels by 88 ± 4%. At the same concentration, OSK3 also inhibits K_v1.6 by 11 ± 3%. The IC50 values for K_v1.2, K_v1.3 and K_v1.6 are 331 ± 17 nM, 503 ± 31nM, and 9983 ± 172 nM respectively.^[2] Higher activity levels on the aforementioned channels has been observed in other well-studied toxins, however this activity level is typical for members of the subfamily such as AmP01 (α-KTx 8.1)^[5] and OdK1 (α-KTx 8.5).^[6]

Mode of action

OSK3 selectively blocks K_v1.2 and K_v1.3. The underlying mechanism for the high affinity of OSK3 for these channels depends on the non-specific hydrophobic interactions between the C-terminal residues of OSK3 and the channel proteins, contrary to many other highly selective ligand-receptor complexes which mostly depend on specific contacts such as hydrogen bonds and salt bridges.^[2]^[7] It is suggested that toxins of the α-KTx8 family specifically bind to the potassium channel vestibule.^[2]

References

↑ ^1.0 ^1.1 "Potassium channel toxin alpha-KTx 8.8 - Orthochirus scrobiculosus (Central Asian scorpion)". https://www.uniprot.org/uniprot/A0A1L2FZD4.
↑ ^2.0 ^2.1 ^2.2 ^2.3 ^2.4 ^2.5 Kuzmenkov, Alexey I.; Peigneur, Steve (2017). "C-Terminal residues in small potassium channel blockers OdK1 and OSK3 from scorpion venom fine-tune the selectivity.". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 1865 (5): 465–472. doi:10.1016/j.bbapap.2017.02.001. PMID 28179135. https://www.sciencedirect.com/science/article/pii/S157096391730016X. Retrieved 2021-10-11.
↑ "A0A1L2FZD4". https://www.ebi.ac.uk/interpro/protein/UniProt/A0A1L2FZD4/sequence/#1-57.
↑ Kuzmenkov, Alexey I.; Krylov, Nikolay A. (April 2016). ""Kalium: A Database of Potassium Channel Toxins from Scorpion Venom."". Database: The Journal of Biological Databases and Curation 2016: baw056. doi:10.1093/database/baw056. PMID 27087309. PMC 4834203. https://www.researchgate.net/publication/301352846. Retrieved 2021-10-11.
↑ Zerrouk; Laraba-Djebari (2009). "Characterization of PO1 a new peptide ligand of the apamin-sensitive Ca2+ activated K+ channel.". International Journal of Peptide and Protein Research 48 (6): 514–521. doi:10.1111/j.1399-3011.1996.tb00870.x. PMID 8985784. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1399-3011.1996.tb00870.x?af=R. Retrieved 2021-10-11.
↑ Abdel-Mottaleb, Yousra; Clynen, Elke (2006-11-13). "The First Potassium Channel Toxin from the Venom of the Iranian Scorpion Odonthobuthus Doriae". FEBS Letters 580 (26): 6254–6258. doi:10.1016/j.febslet.2006.10.029. PMID 17070524. https://www.sciencedirect.com/science/article/pii/S0014579306012439. Retrieved 2021-10-11.
↑ Kuzmenkov, A.I.; Grishin, E.V. (2016-01-05). "Diversity of Potassium Channel Ligands: Focus on Scorpion Toxins.". Biochemistry (Moscow) 80 (13): 1764–1799. doi:10.1134/s0006297915130118. PMID 26878580. https://link.springer.com/article/10.1134/S0006297915130118. Retrieved 2021-10-11.

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Original source: https://en.wikipedia.org/wiki/OSK3. Read more

[first-1] 1.0 ^1.1 "Potassium channel toxin alpha-KTx 8.8 - Orthochirus scrobiculosus (Central Asian scorpion)". https://www.uniprot.org/uniprot/A0A1L2FZD4.

[second-2] 2.0 ^2.1 ^2.2 ^2.3 ^2.4 ^2.5 Kuzmenkov, Alexey I.; Peigneur, Steve (2017). "C-Terminal residues in small potassium channel blockers OdK1 and OSK3 from scorpion venom fine-tune the selectivity.". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 1865 (5): 465–472. doi:10.1016/j.bbapap.2017.02.001. PMID 28179135. https://www.sciencedirect.com/science/article/pii/S157096391730016X. Retrieved 2021-10-11.

[seventh-3] "A0A1L2FZD4". https://www.ebi.ac.uk/interpro/protein/UniProt/A0A1L2FZD4/sequence/#1-57.

[third-4] Kuzmenkov, Alexey I.; Krylov, Nikolay A. (April 2016). ""Kalium: A Database of Potassium Channel Toxins from Scorpion Venom."". Database: The Journal of Biological Databases and Curation 2016: baw056. doi:10.1093/database/baw056. PMID 27087309. PMC 4834203. https://www.researchgate.net/publication/301352846. Retrieved 2021-10-11.

[fourth-5] Zerrouk; Laraba-Djebari (2009). "Characterization of PO1 a new peptide ligand of the apamin-sensitive Ca2+ activated K+ channel.". International Journal of Peptide and Protein Research 48 (6): 514–521. doi:10.1111/j.1399-3011.1996.tb00870.x. PMID 8985784. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1399-3011.1996.tb00870.x?af=R. Retrieved 2021-10-11.

[fifth-6] Abdel-Mottaleb, Yousra; Clynen, Elke (2006-11-13). "The First Potassium Channel Toxin from the Venom of the Iranian Scorpion Odonthobuthus Doriae". FEBS Letters 580 (26): 6254–6258. doi:10.1016/j.febslet.2006.10.029. PMID 17070524. https://www.sciencedirect.com/science/article/pii/S0014579306012439. Retrieved 2021-10-11.

[sixth-7] Kuzmenkov, A.I.; Grishin, E.V. (2016-01-05). "Diversity of Potassium Channel Ligands: Focus on Scorpion Toxins.". Biochemistry (Moscow) 80 (13): 1764–1799. doi:10.1134/s0006297915130118. PMID 26878580. https://link.springer.com/article/10.1134/S0006297915130118. Retrieved 2021-10-11.

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