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Kaliotoxin

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The amino acid sequence of Kaliotoxin
N - Gly - Val - Glu - Ile - Asn - Val - Lys - Cys - Ser - Gly - Ser - Pro - Gln - Cys - Leu - Lys - Pro - Cys - Lys - Asp - Ala - Gly - Met - Arg - Phe - Gly - Lys - Cys - Met - Asn - Arg - Lys - Cys - His - Cys - Thr - Pro - Lys - OH

Kaliotoxin (KTX) inhibits potassium flux through the Kv1.3 voltage-gated potassium channel and calcium-activated potassium channels by physically blocking the channel-entrance and inducing a conformational change in the K+-selectivity filter of the channel.[1]

Sources

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KTX is a neurotoxin derived from the scorpion Androctonus mauretanicus mauretanicus, which is found in the Middle East and North Africa.[2]

Chemistry

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Kaliotoxin is a 4-kDa polypeptide chain, containing 38 amino acids. The formula is C171H283N55O49S8. The sequence has a large homology with iberiotoxin from Buthus tumulus, charybdotoxin from Leiurus quinquestriatus and noxiustoxin from Centruroides noxius. An Important site of the toxin is the K27 side chain (a lysine at place 27 of the protein sequence), which enters the pore and protrudes into the selectivity filter of the channel.[3][4]

Target

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KTX binds to the Kv1.3 voltage-gated potassium channel and the Calcium-activated potassium channels (BK channels).[3][2][5][6] These channels control several regulating processes, including neurotransmitter release, heart rate, insulin secretion, smooth muscle contraction.[7] Kv1.3 channels also play a critical role in regulating the function of effector memory T cells, the subset implicated in many autoimmune disorders, and blockade of Kv1.3 channels by kaliotoxin ameliorates disease in rat models of multiple sclerosis and bone resorption due to periodontitis.[8][9][10]

Mode of action

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The toxin binds to the external vestibule of the channel, and a critical lysine residue (K27), protrudes into the pore and plugs it.[6][11] The positively charged amino-group of the K27 chain fits into the selectivity filter near the G77 chain (Glycine) of the channel, causing a conformational change of the channels´ selectivity filter.[11] Thereby the hydrophobic groups of the K27 side chain replace water molecules in the entry region of the pore. So the pore is blocked by a direct plug into the pore region of the channel and a conformational change in the selectivity filter is induced. By determining the solution structure of kaliotoxin and related toxins, and by using complementary mutagenesis and electrostatic compliance, it was possible to determine the architecture of the toxin binding site at the outer vestibule of the Kv1.3 channel.[6][11] This vestibule is - 28-32 A wide at its outer margin, - 28-34 A wide at its base, and -4-8 A deep; the pore is 9-14 ~A wide at its external entrance and tapers to a width of 4-5 A at a depth of - 5-7 A from the vestibule.[6][11] These dimensions are remarkably similar to that of the outer vestibule of the KcsA bacterial channel that was determined by X-ray crystallography [12][13][3][14]

References

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  1. ^ Yu, Kunqian; Fu, Wei; Liu, Hong; Luo, Xiaomin; Chen, Kai Xian; Ding, Jianping; Shen, Jianhua; Jiang, Hualiang (2004). "Computational Simulations of Interactions of Scorpion Toxins with the Voltage-Gated Potassium Ion Channel". Biophysical Journal. 86 (6): 3542–3555. Bibcode:2004BpJ....86.3542Y. doi:10.1529/biophysj.103.039461. PMC 1304258. PMID 15189853.
  2. ^ a b Crest, M; Jacquet, G; Gola, M; Zerrouk, H; Benslimane, A; Rochat, H; Mansuelle, P; Martin-Eauclaire, M F (1992). "Kaliotoxin, a novel peptidyl inhibitor of neuronal BK-type Ca(2+)-activated K+ channels characterized from Androctonus mauretanicus mauretanicus venom". Journal of Biological Chemistry. 267 (3). Elsevier BV: 1640–1647. doi:10.1016/s0021-9258(18)45993-5. ISSN 0021-9258.
  3. ^ a b c Lange, Adam; Giller, Karin; Hornig, Sönke; Martin-Eauclaire, Marie-France; Pongs, Olaf; Becker, Stefan; Baldus, Marc (2006). "Toxin-induced conformational changes in a potassium channel revealed by solid-state NMR". Nature. 440 (7086): 959–962. Bibcode:2006Natur.440..959L. doi:10.1038/nature04649. ISSN 1476-4687. PMID 16612389. Retrieved 2024-07-31.
  4. ^ Korukottu, Jegannath; Schneider, Robert; Vijayan, Vinesh; Lange, Adam; Pongs, Olaf; Becker, Stefan; Baldus, Marc; Zweckstetter, Markus (2008-06-04). "High-Resolution 3D Structure Determination of Kaliotoxin by Solid-State NMR Spectroscopy". PLOS ONE. 3 (6): e2359. Bibcode:2008PLoSO...3.2359K. doi:10.1371/journal.pone.0002359. ISSN 1932-6203. PMC 2387072. PMID 18523586.
  5. ^ Zachariae, Ulrich; Schneider, Robert; Velisetty, Phanindra; Lange, Adam; Seeliger, Daniel; Wacker, Sören J.; Karimi-Nejad, Yasmin; Vriend, Gert; Becker, Stefan; Pongs, Olaf; Baldus, Marc; de Groot, Bert L. (2008). "The Molecular Mechanism of Toxin-Induced Conformational Changes in a Potassium Channel: Relation to C-Type Inactivation". Structure. 16 (5). Elsevier BV: 747–754. doi:10.1016/j.str.2008.01.018. hdl:11858/00-001M-0000-0012-DBFE-1. ISSN 0969-2126. PMID 18462679.
  6. ^ a b c d Aiyar, Jayashree; Withka, Jane M.; Rizzi, James P.; Singleton, David H.; Andrews, Glenn C.; Lin, Wen; Boyd, James; Hanson, Douglas C.; Simon, Mariella; Dethlefs, Brent; Lee, Chao-lin; Hall, James E.; Gutman, George A.; George Chandy, K. (1995). "Topology of the pore-region of a K+ channel revealed by the NMR-derived structures of scorpion toxins". Neuron. 15 (5). Elsevier BV: 1169–1181. doi:10.1016/0896-6273(95)90104-3. ISSN 0896-6273. PMID 7576659.
  7. ^ Wickenden, Alan D (2002). "K+ channels as therapeutic drug targets". Pharmacology & Therapeutics. 94 (1–2). Elsevier BV: 157–182. doi:10.1016/s0163-7258(02)00201-2. ISSN 0163-7258. PMID 12191600.
  8. ^ Beeton, Christine; Barbaria, Jocelyne; Giraud, Pierre; Devaux, Jerome; Benoliel, Anne-Marie; Gola, Maurice; Sabatier, Jean Marc; Bernard, Dominique; Crest, Marcel; Béraud, Evelyne (2001-01-15). "Selective Blocking of Voltage-Gated K+ Channels Improves Experimental Autoimmune Encephalomyelitis and Inhibits T Cell Activation". The Journal of Immunology. 166 (2). The American Association of Immunologists: 936–944. doi:10.4049/jimmunol.166.2.936. ISSN 0022-1767. PMID 11145670.
  9. ^ Valverde, Paloma; Kawai, Toshihisa; Taubman, Martin A (2004-01-01). "Selective Blockade of Voltage-Gated Potassium Channels Reduces Inflammatory Bone Resorption in Experimental Periodontal Disease". Journal of Bone and Mineral Research. 19 (1): 155–164. doi:10.1359/jbmr.0301213. ISSN 0884-0431. PMID 14753747.
  10. ^ Cahalan, Michael D.; Chandy, K. George (2009). "The functional network of ion channels in T lymphocytes". Immunological Reviews. 231 (1): 59–87. doi:10.1111/j.1600-065X.2009.00816.x. ISSN 0105-2896. PMC 3133616. PMID 19754890.
  11. ^ a b c d Aiyar, Jayashree; Rizzi, James P.; Gutman, George A.; Chandy, K. George (1996). "The Signature Sequence of Voltage-gated Potassium Channels Projects into the External Vestibule". Journal of Biological Chemistry. 271 (49). Elsevier BV: 31013–31016. doi:10.1074/jbc.271.49.31013. ISSN 0021-9258. PMID 8940091.
  12. ^ Doyle, Declan A.; Cabral, João Morais; Pfuetzner, Richard A.; Kuo, Anling; Gulbis, Jacqueline M.; Cohen, Steven L.; Chait, Brian T.; MacKinnon, Roderick (1998-04-03). "The Structure of the Potassium Channel: Molecular Basis of K + Conduction and Selectivity". Science. 280 (5360): 69–77. Bibcode:1998Sci...280...69D. doi:10.1126/science.280.5360.69. ISSN 0036-8075. PMID 9525859.
  13. ^ MacKinnon, Roderick; Cohen, Steven L.; Kuo, Anling; Lee, Alice; Chait, Brian T. (1998-04-03). "Structural Conservation in Prokaryotic and Eukaryotic Potassium Channels". Science. 280 (5360): 106–109. Bibcode:1998Sci...280..106M. doi:10.1126/science.280.5360.106. ISSN 0036-8075. PMID 9525854.
  14. ^ Catterall, William A.; Cestèle, Sandrine; Yarov-Yarovoy, Vladimir; Yu, Frank H.; Konoki, Keiichi; Scheuer, Todd (2007). "Voltage-gated ion channels and gating modifier toxins" (PDF). Toxicon. 49 (2). Elsevier BV: 124–141. Bibcode:2007Txcn...49..124C. doi:10.1016/j.toxicon.2006.09.022. ISSN 0041-0101. PMID 17239913.
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