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

Voltage-gated potassium channel

Voltage-gated potassium channels 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....

 and calcium-activated potassium channels

Calcium-activated potassium channel

Calcium-activated potassium channels are divided into BK channels, IK channels, and SK channels based on their conductance ....

 by physically blocking the channel-entrance and inducing a conformational change

Conformational change

A macromolecule is usually flexible and dynamic. It can change its shape in response to changes in its environment or other factors; each possible shape is called a conformation, and a transition between them is called a conformational change...

 in the K⁺-selectivity filter of the channel.

Source

KTX is a neurotoxin

Neurotoxin

A neurotoxin is a toxin that acts specifically on nerve cells , usually by interacting with membrane proteins such as ion channels. Some sources are more general, and define the effect of neurotoxins as occurring at nerve tissue...

 derived from the scorpion Androctonus mauretanicus mauretanicus, which is found in the Middle East

Middle East

The Middle East is a region that encompasses Western Asia and Northern Africa. It is often used as a synonym for Near East, in opposition to Far East...

 and North Africa

North Africa

North Africa or Northern Africa is the northernmost region of the African continent, linked by the Sahara to Sub-Saharan Africa. Geopolitically, the United Nations definition of Northern Africa includes eight countries or territories; Algeria, Egypt, Libya, Morocco, South Sudan, Sudan, Tunisia, and...

. (Crest M et al.)

Chemistry

Kaliotoxin is a 4-kDa polypeptide chain, containing 38 amino acids. The sequence has a large homology

Homology (biology)

Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...

 with iberiotoxin

Iberiotoxin

Iberiotoxin is an ion channel toxin purified from the Eastern Indian red scorpion Buthus tamulus.Iberiotoxin selectively inhibits the current through large-conductance calcium-activated potassium channels.- Chemistry :...

 from Buthus tumulus, charybdotoxin

Charybdotoxin

Charybdotoxin is a 37 amino acid neurotoxin from the venom of the scorpion Leiurus quinquestriatus hebraeus that blocks calcium-activated potassium channels. This blockade causes hyperexcitability of the nervous system.-Chemical properties:...

 from Leiurus quinquestriatus and noxiustoxin from Centruroides noxius.
An Important site of the toxin is the K27 side chain (a lysine

Lysine

Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....

 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 channel

Voltage-gated potassium channels 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....

 and the Calcium-activated potassium channels (BK channels

BK channel

BK channels , also called Maxi-K or slo1, are ion channels characterized by their large conductance of potassium ions through cell membranes. These channels are activated by changes in membrane electrical potential and/or by increases in concentration of intracellular calcium ion...

). (Lange A et al., Crest M et al., Zachariae U et al., Aiyar J et al.,)
These channels control several regulating processes, including neurotransmitter

Neurotransmitter

Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...

 release, heart rate, insulin

Insulin

Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....

 secretion, smooth muscle

Smooth muscle

Smooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...

 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

Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...

) of the channel, causing a conformational change of the channels´ selectivity filter (Aiyar J et al., 1996). 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 (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.)