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]

Contents

Sources

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

Chemistry

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

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

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]

Related Research Articles

<span class="mw-page-title-main">Kv1.1</span>

Potassium voltage-gated channel subfamily A member 1 also known as Kv1.1 is a shaker related voltage-gated potassium channel that in humans is encoded by the KCNA1 gene. Isaacs syndrome is a result of an autoimmune reaction against the Kv1.1 ion channel.

<span class="mw-page-title-main">Voltage-gated potassium channel</span> Class of transport proteins

Voltage-gated potassium channels (VGKCs) are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a crucial role in returning the depolarized cell to a resting state.

<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">Cobatoxin</span> Chemical compound

Cobatoxin is a toxin present in the venom of the scorpion Centruroides noxius. It blocks two potassium channel subtypes; voltage-gated and calcium-activated channels.

<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.

<span class="mw-page-title-main">Lq2</span>

Lq2 is a component of the venom of the scorpion Leiurus quinquestriatus. It blocks various potassium channels, among others the inward-rectifier potassium ion channel ROMK1.

<span class="mw-page-title-main">KcsA potassium channel</span> Prokaryotic potassium ion channel

KcsA (K channel of streptomyces A) is a prokaryotic potassium channel from the soil bacterium Streptomyces lividans that has been studied extensively in ion channel research. The pH activated protein possesses two transmembrane segments and a highly selective pore region, responsible for the gating and shuttling of K+ ions out of the cell. The amino acid sequence found in the selectivity filter of KcsA is highly conserved among both prokaryotic and eukaryotic K+ voltage channels; as a result, research on KcsA has provided important structural and mechanistic insight on the molecular basis for K+ ion selection and conduction. As one of the most studied ion channels to this day, KcsA is a template for research on K+ channel function and its elucidated structure underlies computational modeling of channel dynamics for both prokaryotic and eukaryotic species.

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

Pandinotoxins are toxins from the venom of the emperor scorpion Pandinus imperator. They are selective blockers of voltage-gated potassium channels

Anuroctoxin is a peptide from the venom of the Mexican scorpion Anuroctonus phaiodactylus. This neurotoxin belongs to the alpha family of potassium channel acting peptides. It is a high-affinity blocker of Kv1.3 channels.

Butantoxin (BuTX) is a compound of the venom of three Brazilian and an Argentinean scorpion species of the genus Tityus. Butantoxin reversibly blocks the voltage-gated K+ channels Shaker B and Kv1.2, and the Ca2+-activated K+ channelsKCa 1.1 and KCa 3.1.

<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.

AmmTX3, produced by Androctonus mauretanicus, is a scorpion toxin of the α-KTX15 subfamily. The toxin is known for its ability to act as a specific Kv4 channel blocker, and thereby reducing the A-type potassium current through this channel.

Spinoxin is a 34-residue peptide neurotoxin isolated from the venom of the Malaysian black scorpion Heterometrus spinifer. It is part of the α-KTx6 subfamily and exerts its effects by inhibiting voltage-gated potassium channels, specifically Kv1.2 and Kv1.3.

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

<span class="mw-page-title-main">ImKTx88</span>

ImKTx88 is a selective inhibitor of the Kv1 ion channel family that can be isolated from the venom of the Isometrus maculatus. This peptide belongs to the α-KTx subfamily and is classified as a pore-blocking toxin.

MeuKTX, which belongs to the α-KTx toxin subfamily, is a neurotoxin present in the venom of Mesobuthus eupeus. This short-chain peptide blocks potassium channels, such as Kv1.1, Kv1.2 and Kv1.3.

<span class="mw-page-title-main">OdK2</span>

OdK2 is a toxin found in the venom of the Iranian scorpion Odonthobuthus doriae. It belongs to the α-KTx family, and selectively blocks the voltage-gated potassium channel Kv1.3 (KCNA3).

<span class="mw-page-title-main">OSK3</span>

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 (Kv1.2), and KCNA3 (Kv1.3).

BmKTX is a scorpion neurotoxin which blocks the voltage gated potassium channel Kv1.3.

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. ↑ 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. 1 2 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. 1 2 3 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. ISSN   0969-2126. PMID   18462679.
  6. 1 2 3 4 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. 1 2 3 4 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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