Kaliotoxin
   HOME

TheInfoList



OR:

{, style="float: right; clear: right; margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" align="right" width="280" !The amino acid sequence of Kaliotoxin , - , bgcolor="#eeeeee" , 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 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 ce ...
and
calcium-activated potassium channel Calcium-activated potassium channels are potassium channels gated by calcium, or that are structurally or phylogenetically related to calcium gated channels. They were first discovered in 1958 by Gardos who saw that calcium levels inside of a cell ...
s by physically blocking the channel-entrance and inducing a
conformational change In biochemistry, a conformational change is a change in the shape of a macromolecule, often induced by environmental factors. A macromolecule is usually flexible and dynamic. Its shape can change in response to changes in its environment or oth ...
in the K+- selectivity filter of the channel.


Sources

KTX is a
neurotoxin Neurotoxins are toxins that are destructive to nerve tissue (causing neurotoxicity). Neurotoxins are an extensive class of exogenous chemical neurological insultsSpencer 2000 that can adversely affect function in both developing and mature ner ...
derived from the scorpion Androctonus mauretanicus mauretanicus, which is found in the
Middle East The Middle East ( ar, الشرق الأوسط, ISO 233: ) is a geopolitical region commonly encompassing Arabian Peninsula, Arabia (including the Arabian Peninsula and Bahrain), Anatolia, Asia Minor (Asian part of Turkey except Hatay Pro ...
and
North Africa North Africa, or Northern Africa is a region encompassing the northern portion of the African continent. There is no singularly accepted scope for the region, and it is sometimes defined as stretching from the Atlantic shores of Mauritania in ...
. (Crest M et al.)


Chemistry

Kaliotoxin is a 4-kDa polypeptide chain, containing 38
amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
. The formula is C171H283N55O49S8. The sequence has a large
homology Homology may refer to: Sciences Biology *Homology (biology), any characteristic of biological organisms that is derived from a common ancestor * Sequence homology, biological homology between DNA, RNA, or protein sequences *Homologous chrom ...
with
iberiotoxin Iberiotoxin (IbTX) is an ion channel toxin purified from the Eastern Indian red scorpion ''Hottentotta tamulus''. Iberiotoxin selectively inhibits the current through large-conductance calcium-activated potassium channels. Chemistry Iberiotoxin ...
from ''Buthus tumulus'',
charybdotoxin Charybdotoxin (CTX) is a 37 amino acid neurotoxin from the venom of the scorpion '' Leiurus quinquestriatus hebraeus'' (''deathstalker'') that blocks calcium-activated potassium channels. This blockade causes hyperexcitability of the nervous syst ...
from ''Leiurus quinquestriatus'' and noxiustoxin from ''Centruroides noxius''. An Important site of the toxin is the K27 side chain (a
lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...
at place 27 of the protein sequence), which enters the pore and protrudes into the selectivity filter of the channel. (Lange A et al., Korukottu J et al.)


Target

KTX binds to the Kv1.3
voltage-gated potassium channel 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 ce ...
and the Calcium-activated potassium channels (
BK channel BK channels (big potassium), are large conductance calcium-activated potassium channels, also known as Maxi-K, slo1, or Kca1.1. BK channels are voltage-gated potassium channels that conduct large amounts of potassium ions (K+) across the ce ...
s). (Lange A et al., Crest M et al., Zachariae U et al., Aiyar J et al.,) These channels control several regulating processes, including
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neuro ...
release, heart rate,
insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
secretion,
smooth muscle Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit mus ...
contraction. (Wickenden A et al.) 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. (Beeton C et al., Valverde P et al., Cahalan and Chandy)


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 (Aiyar J et al., 1995, 1996). The positively charged amino-group of the K27 chain fits into the selectivity filter near the G77 chain (
Glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
) of the channel, causing a conformational change of the channels´ selectivity filter (Aiyar J et al., 1996). Thereby the
hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, th ...
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 (Aiyar J et al., 1995, 1996). 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 (Aiyar J et al., 1995, 1996). These dimensions are remarkably similar to that of the outer vestibule of the KcsA bacterial channel that was determined by X-ray crystallography (Doyle et al., MacKinnon et al., Lange A et al., Catterall WA et al.)


References

1. Korukottu J et al., High-resolution 3D structure determination of kaliotoxin by solid-state NMR spectroscopy
PLoS ONE. 2008 Jun 4;3(6):e2359
/small> 2. Zachariae U et al., The molecular mechanism of toxin-induced conformational changes in a potassium channel: relation to C-type inactivation
Structure. 2008 May;16(5):747-54
/small> 3. Catterall WA et al., Voltage-gated ion channels and gating modifier toxins
Toxicon. 2007 Feb;49(2):124-41
/small> 4. Lange A et al., Toxin-induced conformational changes in a potassium channel revealed by solid-state NMR

/small> 5. Kunqian Y et al., Computational simulations of interactions of scorpion toxins with the voltage-gated potassium ion channel
Biophys J. 2004 Jun;86(6):3542-55
/small> 6. Wickenden A et al., K(+) channels as therapeutic drug targets. Pharmacol Ther. 2002 Apr-May;94(1-2):157-82. 7. Crest M et al., Kaliotoxin, a novel peptidyl inhibitor of neuronal BK-type Ca(2+)-activated K+ channels characterized from Androctonus mauretanicus mauretanicus venom
J Biol Chem. 1992 Jan 25;267(3):1640-7
/small> 8. Aiyar J et al., Topology of the pore-region of a K+ channel revealed by the NMR-derived structures of scorpion toxins. euron 1995 15:1169-1181/small> 9. Aiyar J. et al., The signature sequence of voltage-gated potassium channels projects into the external vestibule. Biol Chem. 1996 Dec 6;271(49):31013-6/small> 10. Beeton C et al., Selective blocking of voltage-gated K+ channels improves experimental autoimmune encephalomyelitis and inhibits T cell activation. Immunol. 2001 Jan 15;166(2):936-44/small> 11. Valverde P et al., Selective blockade of voltage-gated potassium channels reduces inflammatory bone resorption in experimental periodontal disease. Bone Miner Res. 2004 Jan;19(1):155-64./small> 12. Cahalan MD and Chandy KG. The functional network of ion channels in T lymphocytes. mmunol Rev. 2009 Sep;231(1):59-87./small> 13. Doyle DA et al., The structure of the potassium channel: molecular basis of K+ conduction and selectivity. cience. 1998 Apr 3;280(5360):69-77/small> 14. MacKinnon R et al., Structural conservation in prokaryotic and eukaryotic potassium channels. cience. 1998 Apr 3;280(5360):106-9/small> Ion channel toxins