Summary: ShK domain-like
This is the Wikipedia entry entitled "Stichodactyla toxin". More...
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Stichodactyla toxin Edit Wikipedia article
ShK is a 35-residue basic peptide first discovered in the sea anemone Stichodactyla helianthus by Professor Olga Castaneda from the University of Havana, Cuba, and her collaborators in Sweden. The formula is C169H274N54O48S7. It is cross-linked by three disulfide bridges: Cys3-Cys35, Cys12-Cys28, and Cys17-Cys32 (see figure below). The amino acid sequence of the ShK toxin is Arg-Ser-Cys-Ile-Asp-Thr-Ile-Pro-Lys-Ser-Arg-Cys-Thr-Ala-Phe-Gln-Cys-Lys-His-Ser-Met-Lys-Tyr-Arg-Leu-Ser-Phe-Cys-Arg-Lys-Thr-Cys-Gly-Thr-Cys. ShK is stabilized by three disulfide bridges and consists of two short α-helices comprising residues 14-19 and 21-24. The N-terminal eight residues of ShK adopt an extended conformation, followed by a pair of interlocking turns that resemble a 310 helix, while its C-terminal Cys35 residue forms a nearly head-to-tail cyclic structure through a disulfide bond with Cys3. Protein domains with structural resemblance to ShK have been described in 402 proteins, most of them from C. elegans (IPR003582). The SMART database at the EMBL has a list of the 402 proteins containing ShK-like sequences (http://smart.embl-heidelberg.de). Other proteins containing domains with similar structures include the cysteine-rich secretory protein snake toxins natrin, triflin, and stecrisp, the Toxocara canis mucins, secreted peptides from the dog hookworm Ancylostoma caninum, and the human proteins Tpx-1 and matrix metalloprotease 23 (MMP23)  The peptide binds to all four subunits in the Kv1.3 tetramer through its interaction with the shallow vestibule at the outer entrance of the ion conduction pathway. The peptide's Lysine22 residue occludes the channel pore like a "cork in a bottle". This blocks the entrance to the pore.
ShK blocks the Kv1.3 channel in T cells with a Kd of about 11 pM. It blocks the neuronal Kv1.1 and Kv1.6 channels with Kds of 16 pM and 200 pM respectively. The Kv3.2 and KCa3.1 channels are more than 1000 times less sensitive to the peptide.
Several ShK analogs have been generated to enhance specificity for the Kv1.3 channel over the Kv1.1, Kv1.6 and Kv3.2 channels. The first analog that showed some degree of specificity was ShK-Dap22. Attaching a fluorescein to the N-terminus of the peptide via a hydrophilic AEEA linker (2-aminoethoxy-2-ethoxy acetic acid; mini-PEG) resulted in a peptide, ShK-F6CA, with 100-fold specificity for Kv1.3 over Kv1.1 and related channels. Based on this surprising finding additional analogs were made. ShK-170 [a.k.a. ShK(L5)],contains a L-phosphotyrosine in place of the fluorescein in ShK-F6CA. It blocks Kv1.3 with a Kd of 69 pM and shows exquisite specificity for Kv1.3. However, it is chemically unstable. To improve stability a new analog, ShK-186 [a.k.a. SL5], was made with the C-terminal carboxyl of ShK-170 replaced by an amide; ShK-186 is otherwise identical to ShK-170. In rats and squirrel monkeys, an indium-labeled ShK-186 analog called ShK-221, was slowly released from the injection site and maintained blood levels above the channel blocking dose for 3–5 days Tarcha EJ, Chi V, Muñoz-Elias EJ, Bailey D, Londono LM, Upadhyay SK, Norton KN, Olson A, Tjong I, Nguyen HM, Hu X, Rupert GW, Boley SE, Slauter R, Sams J, Knapp B, Kentala D, Hansen Z, Pennington MW, Beeton C, Chandy KG, Iadonato SP (2012). "Durable pharmacological responses from a single dose of the peptide drug ShK-186, a specific Kv1.3 channel inhibitor". J. Pharm. Exp. Therap 342: 642–653. doi:10.1124/jpet.112.191890. PMID 22637724.</ref> ShK-192 is a new analog with increased stability. It contains norleucine21 in place of methionine21 to avoid methionine oxidation, and the terminal phosphotyrosine is replaced by a non-hydrolyzable para-phosphonophenylalanine (Ppa) group. ShK-192 is effective in ameliorating disease in rat models of multiple sclerosis. The D-diasteromer of ShK is also stable but blocks Kv1.3 with 2800-fold potency than the L-form (Kd = 36 nM) and it only exhibits 2-fold specificity for Kv1.3 over Kv1.1.
Kv1.3 and KCa3.1 regulate membrane potential and calcium signaling of T cells. Calcium entry through the CRAC channel is promoted by potassium efflux through the Kv1.3 and KCa3.1 potassium channels. Blockade of Kv1.3 channels in effector-memory T cells by ShK-186 suppresses calcium signaling, cytokine production (interferon-gamma, interleukin 2) and cell proliferation. In vivo, ShK-186 paralyzes effector-memory T cells at the sites of inflammation and prevent their reactivation in inflamed tissues. In contrast, ShK-186 does not affect the homing to and motility within lymph nodes of naive and central memory T cells, most likely because these cells express the KCa3.1 channel and are therefore protected from the effect of Kv1.3 blockade. In proof-of-concept studies, ShK and its analogs have prevented and treated disease in rat models of multiple sclerosis, rheumatoid arthritis, and delayed type hypersensitivity. ShK-186, due to its durable pharmacological action, is effective in ameliorating disease in rat models of delayed type hypersensitivity, multiple sclerosis (experimental autoimmune encephalomyelitis) and rheumatoid arthritis (pristane induced arthritis) when administered once every 2–5 days. ShK-186 has completed non-clinical safety studies as is being evaluated in phase 1 human trials.
As ShK toxin binds to the synaptosomal membranes, it facilitates an acetylcholine release at avian neuromuscular junctions while the Kv3.2 channels are expressed in neurons that fire at a high frequency (such as cortical GABAergic interneurons), due to their fast activation and deactivation rates. By blocking Kv3.2, ShK toxin depolarises the cortical GABAergic interneurons. Kv3.2 is also expressed in pancreatic beta cells. These cells are thought to play a role in their delayed-rectifier current, which regulates glucose-dependent firing. Therefore, ShK, as a Kv3.2 blocker, might be useful in the treatment of type-2 diabetes, although inhibition of the delayed-rectifier current has not yet been observed in human cells even when very high ShK concentrations were used.
Toxicity of ShK toxin in mice is quite low. The median paralytic dose is about 25 mg/kg bodyweight (which translates to 0.5 mg per 20 g mouse). In rats the therapeutic safety index was greater than 75-fold.
ShK-Dap22 is less toxic, even a dose of 1.0 mg dose did not cause hyperactivity, seizures or mortality. The median paralytic dose was 200 mg/kg body weight.
ShK-170 [a.k.a. ShK(L5)] does not cause significant toxicity in vitro. The peptide was not toxic to human and rat lymphoid cells incubated for 48 h with 100 nM of ShK-170 (>1200 times greater than the Kv1.3 half-blocking dose). The same high concentration of ShK-170 was negative in the Ames test on tester strain TA97A, suggesting that it is not a mutagen. ShK-170 had no effect on heart rate or heart rate variability parameters in either the time or the frequency domain in rats. It does not block the hERG (Kv11.1) channel that is associated with drug-associated cardiac arrhythmias. Repeated daily administration of the peptide by subcutaneous injection (10 µg/kg/day) for 2 weeks to rats does not cause any changes in blood counts, blood chemistry or in the proportion of thymocyte or lymphocyte subsets. Furthermore, the rats administered the peptide gain weight normally.
ShK-186 [a.k.a. SL5] is also safe. Repeated daily administration by subcutaneous injection of ShK-186 (100 µg/kg/day) for 4 weeks to rats does not cause any changes in blood counts, blood chemistry or histopathology. Furthermore, ShK-186 did not compromise the protective immune response to acute influenza viral infection or acute bacterial (Chlamydia) infection in rats at concentrations that were effective in ameliorating autoimmune diseases in rat models. Interestingly, rats repeatedly administered ShK-186 for a month by subcutaneous injection (500 µg/kg/day) developed low titer anti-ShK antibodies. The reason for the low immunogenicity of the peptide is not well understood. ShK-186 has completed GLP (Good Laboratory Practice) non-clinical safety studies in rodents and non-human primates, and ShK-186 is currently being evaluated in phase 1 human trials.
Many groups are developing Kv1.3 blockers for the treatment of autoimmune diseases.
Because ShK toxin is a specific inhibitor of Kv1.1, Kv1.3, Kv1.6, Kv3.2 and KCa3.1, it may serve as a useful pharmacological tool for studying these channels. The Kv1.3 specific ShK analogs, ShK-170, ShK-186 and ShK-192, have been demonstrated to be effective in rat models of autoimmune diseases, and these or related analogs might have use as therapeutics for human autoimmune diseases.
Kv1.3 is also considered a therapeutic target for the treatment of obesity, for enhancing peripheral insulin sensitivity in patients with type-2 diabetes mellitus, and for preventing bone resorption in periodontal disease. Furthermore, because pancreatic beta cells, which have Kv3.2 channels, are thought to play a role in glucose-dependent firing, ShK, as a Kv3.2 blocker, might be useful in the treatment of type-2 diabetes, although inhibition of the delayed-rectifier current has not yet been observed in human cells even when very high ShK concentrations were used.
- PDB 1ROO; Tudor JE, Pallaghy PK, Pennington MW, Norton RS (April 1996). "Solution structure of ShK toxin, a novel potassium channel inhibitor from a sea anemone". Nat. Struct. Biol. 3 (4): 317–20. doi:10.1038/nsb0496-317. PMID 8599755.
- Castañeda O, Sotolongo V, Amor AM, Stöcklin R, Anderson AJ, Harvey AL, Engström A, Wernstedt C, Karlsson E (May 1995). "Characterization of a potassium channel toxin from the Caribbean Sea anemone Stichodactyla helianthus". Toxicon 33 (5): 603–13. doi:10.1016/0041-0101(95)00013-C. PMID 7660365.
- Pennington MW, Mahnir VM, Khaytin I, Zaydenberg I, Byrnes ME, Kem WR (December 1996). "An essential binding surface for ShK toxin interaction with rat brain potassium channels". Biochemistry 35 (51): 16407–11. doi:10.1021/bi962463g. PMID 8987971.
- Pennington MW, Lanigan MD, Kalman K, Mahnir VM, Rauer H, McVaugh CT, Behm D, Donaldson D, Chandy KG, Kem WR, Norton RS (November 1999). "Role of disulfide bonds in the structure and potassium channel blocking activity of ShK toxin". Biochemistry 38 (44): 14549–58. doi:10.1021/bi991282m. PMID 10545177.
- Pohl J, Hubalek F, Byrnes ME, Nielsen KR, Woods A and Pennington MW (1995). "Assignment of the three disulfide bonds in ShK toxin: A potent potassium channel inhibitor from the sea anemone Stichodactyla helianthus". Letters in Peptide Science 1 (6): 291–297. doi:10.1007/BF00119770
- Wang F, Li H, Liu MN, Song H, Han HM, Wang QL, Yin CC, Zhou YC, Qi Z, Shu YY, Lin ZJ, Jiang T (December 2006). "Structural and functional analysis of natrin, a venom protein that targets various ion channels". Biochem. Biophys. Res. Commun. 351 (2): 443–8. doi:10.1016/j.bbrc.2006.10.067. PMID 17070778.
- Shikamoto Y, Suto K, Yamazaki Y, Morita T, Mizuno H (July 2005). "Crystal structure of a CRISP family Ca2+ -channel blocker derived from snake venom". J. Mol. Biol. 350 (4): 735–43. doi:10.1016/j.jmb.2005.05.020. PMID 15953617.
- Guo M, Teng M, Niu L, Liu Q, Huang Q, Hao Q (April 2005). "Crystal structure of the cysteine-rich secretory protein stecrisp reveals that the cysteine-rich domain has a K+ channel inhibitor-like fold". J. Biol. Chem. 280 (13): 12405–12. doi:10.1074/jbc.M413566200. PMID 15596436.
- Gibbs GM, Scanlon MJ, Swarbrick J, Curtis S, Gallant E, Dulhunty AF, O'Bryan MK (February 2006). "The cysteine-rich secretory protein domain of Tpx-1 is related to ion channel toxins and regulates ryanodine receptor Ca2+ signaling". J. Biol. Chem. 281 (7): 4156–63. doi:10.1074/jbc.M506849200. PMID 16339766.
- Loukas A, Hintz M, Linder D, Mullin NP, Parkinson J, Tetteh KK, Maizels RM (December 2000). "A family of secreted mucins from the parasitic nematode Toxocara canis bears diverse mucin domains but shares similar flanking six-cysteine repeat motifs". J. Biol. Chem. 275 (50): 39600–7. doi:10.1074/jbc.M005632200. PMID 10950959.
- Rangaraju S, Khoo KK, Feng ZP, Crossley G, Nugent D, Khaytin I, Chi V, Pham C, Calabresi P, Pennington MW, Norton RS, Chandy KG (March 2010). "Potassium channel modulation by a toxin domain in matrix metalloprotease 23". J Biol Chem 285 (12): 9124–9136. doi:10.1074/jbc.M109.071266. PMID 19965868.
- Loukas A, Prociv P (October 2001). "Immune responses in hookworm infections.". Clin Microbiol Rev. 14 (4): 689–703. doi:10.1128/CMR.14.4.689-703.2001. PMID 11585781.</>
TargetShK toxin blocks the K+ channels Kv1.1, Kv1.3, Kv1.6, Kv3.2 and KCa<3.1,
ShK domain-like Provide feedback
This domain of is found in several C. elegans proteins. The domain is 30 amino acids long and rich in cysteine residues. There are 6 conserved cysteine positions in the domain that form three disulphide bridges. The domain is found in the potassium channel inhibitor ShK in sea anemone .
Tudor JE, Pallaghy PK, Pennington MW, Norton RS; , Nat Struct Biol. 1996;3:317-320.: Solution structure of ShK toxin, a novel potassium channel inhibitor from a sea anemone. PUBMED:8599755 EPMC:8599755
Castaneda O, Sotolongo V, Amor AM, Stocklin R, Anderson AJ, Harvey AL, Engstrom A, Wernstedt C, Karlsson E; , Toxicon. 1995;33:603-613.: Characterization of a potassium channel toxin from the Caribbean Sea anemone Stichodactyla helianthus. PUBMED:7660365 EPMC:7660365
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR003582
The ShK toxin domain is found in metridin, a toxin from Metridium senile (brown sea anemone) and in ShK, a structurally defined polypeptide from the sea anemone Stoichactis helianthus (Stichodactyla helianthus) (Caribbean sea anemone). ShK is a powerful inhibitor of T lymphocyte voltage-gated potassium channels, in particular Kv1.3 [PUBMED:10545177]. It has been proposed that structural analogues may have use as an immunosuppressants for the prevention of graft rejection and for the treatment of autoimmune diseases [PUBMED:9830012].
The ShK toxin domain, is also found in one or more copies as a C-terminal domain in the metallopeptidases of Caenorhabditis elegans. The metallopeptidases belonging to MEROPS peptidase families: M10A, M12A and M14A. The majority belonging to M12A, the astacin/adamalysin family of metallopeptidases.
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Members of this clan include the Crisp domain which is involved in ryanodine receptor Ca2+ signalling, and the ShK domain which is named after the ShK channel inhibitor toxin. Both domains are cysteine rich and contain multiple disulphide bonds .
The clan contains the following 2 members:Crisp ShK
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Curation and family details
|Seed source:||Pfam-B_662 (release 4.0)|
|Author:||Bashton M, Bateman A|
|Number in seed:||157|
|Number in full:||2278|
|Average length of the domain:||36.40 aa|
|Average identity of full alignment:||29 %|
|Average coverage of the sequence by the domain:||22.98 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||19|
|Download:||download the raw HMM for this family|
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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the ShK domain has been found. There are 2 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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