Summary: ShK domain-like
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This is the Wikipedia entry entitled "Stichodactyla toxin". More...
Stichodactyla toxin Edit Wikipedia article
Stichodactyla toxin (ShK) is a peptide toxin that blocks certain voltage-dependent potassium channels.
Contents
Etymology Source Chemistry Target Toxicity Use References
The stichodactyla toxin ShK stems from the sea anemone Stichodactyla Helianthus. The Stichodactyla Helianthus is a large, green, sessile (without a stalk), carpet-like sea anemone, from the Carribean. It lives in shallow areas with mild to strong currents, and associates with clown fish. It is believed that it excretes toxins mainly to protect itself from the spiny lobster (Norton, 2004).
Etymology
Helianthus stems from the Greek words ἡλιος (meaning sun), and ἀνθος, meaning flower. Therefore, Stichodactyla Helianthus is also named the sun anemone.
Source
The stichodactyla toxin (ShK) is a peptide present in the venom of the Stichodactyla Helianthus, a species from the genus of Stichodactyla, which belongs to the order of the Actinaria, more commonly known as sea anemone.
Chemistry
ShK is a 35-residue basic peptide. It is cross-linked by three disulfide bridges: Cys3-Cys35, Cys12-Cys28, and Cys17-Cys32 (Pennington et al. 1999). 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 (Castaneda et al. 1995).
Target
ShK toxin blocks K+ channels. It binds to a shallow vestibule at the outer entrance of the ion conduction pathway. This blocks the entrance to the pore (Norton et al, 2004). As ShK toxin binds to the synaptosomal membranes, it facilitates an acetylcholine release at avian neuromuscular junctions. (Castaneda et al. 1995) Blocking the K+ channels which are the target of ShK (such as Kv1.3) depolarizes the T-cell membrane, which inhibits Ca2+ signaling, therefore inhibiting T-cell activation (Norton, 2004).
ShK blocks the Kv1.1, Kv1.3 and Kv3.2 (voltage-gated potassium) channels (Middleton et al. 2003, Yan et al, 2005). The Kv1.1 and Kv1.3 channels are blocked by ShK at IC50 values of ~1 pM, which is a very low concentration, as compared to the concentration required to inhibit the Kv3.2 (which needs a concentration of about a 1000 times higher) (Yan et al, 2005). The Kv1.3 channels set the resting potential of human T-lymphocytes. Inhibition of these channels causes the cell to depolarize, which results in an increase of intracellular calcium levels. These act to stimulate T cell receptors, which is important for T cell proliferation. Furthermore, Kv1.3 channels are upregulated in activated human effector memory cells (Middelton et al 1993) 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 (Yan et al, 2005). 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 (Yan et al, 2005).
Toxicity
Toxicity of ShK toxin in mice is quite low. The median paralytic dose is about 25mg/kg bodyweight (which translates to 0.5 mg per 20g mouse. ShK-Dap22 is less toxic, even a dose of 0.1 mg dose did not cause hyperactivity, seizures or mortality. The median paralytic dose was 200 mg/kg body weight (Kalman et al, 1998).
Use
Because ShK toxin inhibits very specific potassium channels, it may serve as a useful pharmalogical tool for studying these channels (Yan et al, 2005). Furthermore, patients with multiple sclerosis (MS) have higher levels of Kv1.3 channels in activated, myelin-reactive T cells, compared to naive or central memory T cells. Since Kv1.3 inhibitors, like the ShK toxin, suppress proliferation of T cells, this toxin might serve as a useful tool for studying MS (Middleton et al. 2003). Shk-Dap22, in which Lys22 is replaced with a positively charged, non naturual amino acid diaminopropionic acid, works as a highly selective and very potent blocker of T-lymphocyte Kv1.3 channels. This lead investigators to propose that ShK-Dap22 might serve as an immunosuppressant in the treatment of autoimmune diseases (Kalman et al, 1998). However, other research has argued that the therapeutic utility of ShK-Dap22 might be compromised due to the finding that the potency of ShK-Dap22 is significantly reduced as compared to ShK toxin (Middleton et al, 2003). It is still unknown if ShK, or the derivative ShK-Dap22, has a therapeutic potential, but research so far seems encouraging.
References
(1) Norton, R.S., Pennington, M.W., Wulff, H. (2004). Potassium channel blockade by the sea anemone toxin ShK for the treatment of multiple sclerosis and other autoimmune diseases. Current Medicinal Chemistry, 11, 3041-3052.
(2) Pennington, M.W., Lanigan, M.D.,Kalman, K., Mahnir, V.M., Rauer, H., McVaugh, S.T., Behm, D., Donaldson, D., Chandy, K.G., Kem, W.R., Norton, R.S. (1999) Role of Disulfide Bonds in the Structure and Potassium Channel Blocking Activity of ShK Toxin. Biochemistry, 38, 14549-14558
(3) Castaneda, O., Sotolongo, V., Amor, A.M., Stocklin, R., Anderson, A.M., Harvey, A.L., Engstrom, A., Wernstedt, C., Karlsson, E. (1995) Characterization of a potassium channel toxin from the caribbean sea anemone stichodactyla helianthus. Toxicon, 33, 603-613
(4) Middleton, R.E., Sanchez, M., Linde, A., Bugianesi, R.M., Dai, G., Felix, J.P., Kporak, S.L., Staruch, M.J., Bruguera, M., Cox, R., Ghosh, A., Hwang, J., Jones, S., Kohler, M., Slaugter, R.S., McManus, O.B., Kaczorowski, G,J., Garcia M.L. (2003). Substitutions of a single residue in stichodactyla helianthus peptide, ShK-Dap22 reveals a nvel pharmacological profile. Biochemistry, 42, 13698-13707
(5) Yan, L., Herrington, J., Goldberg, E., Dulski, P.M., Bugianesi, R.M., Slaughter, R.S., Banerjee, P., Brochu, R.M., Priest, B.T., Kaczorowski, G..J., Rudy, B., Garcia, M.L. (2005). Stichodactyla helianthus peptide, a pharmacological tool for studying Kv3.2 channels. Molecular Pharmacology, 67, 1513–1521
(6) Kalman, K., Pennington, M.W., Lanigan, M.D., Nguyen, A., Rauer, H., Mahniri, V., Paschetto, K., Kemi, W.R., Grissmer, S., Gutman, G.A., Christian, E.P., Cahalan, M.D., Norton, R.S., Chandy, K.G. (1998) ShK-Dap22, a Potent Kv1.3-specific Immunosuppressive Polypeptide. The journal of biological chemistry, 49, 32697–32707
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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 [1].
Literature references
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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
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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
| SCOP: | 1roo |
This tab holds annotation information from the InterPro database.
InterPro entry IPR003582
BgK, a 37-residue peptide toxin from the sea anemone Bunodosoma granulifera, and ShK, a 35-residue peptide toxin from the sea anemone Stichodactyla helianthus, are potent inhibitors of K channels. There is a large superfamily of proteins that contains domains (referred to as ShKT domains) resembling these two toxins. Many of these proteins are metallopeptidases, whereas others are prolyl-4-hydroxylases, tyrosinases, peroxidases, oxidoreductases, or proteins containing epidermal growth factor-like domains, thrombospondin-type repeats, or trypsin-like serine protease domains [ PUBMED:19965868 ]. The ShKT domain has also been called NC6 (nematode six-cysteine) domain [ PUBMED:10950959 ], SXC (six-cysteine) domain [ PUBMED:10950959 , PUBMED:11412804 , PUBMED:9851921 , PUBMED:14653817 ] and ICR (ion channel regulator) [ PUBMED:19965868 , PUBMED:16339766 ]. The ShKT domain is short (36 to 42 amino acids), with six conserved cysteines and a number of other conserved residues. The fold adopted by the ShKT domain contains two nearly perpendicular stretches of helices, with no additional canonical secondary structures [ PUBMED:9020148 ]. The globular architecture of the ShKT domain is stabilised by three disulfides, one of them linking the two helices. In venomous creatures, the ShKT domain may have been modified to give rise to potent ion channel blockers, whereas the incorporation of this domain into plant oxidoreductases and prolyl hydroxylases and into worm astacin-like metalloproteases and trypsin-like serine proteases produced enzymes with potential channel-modulatory activity.
Some proteins known to contain a ShKT domain are listed below:
- Caribbean sea anemone ShK, a potassium channel toxin [ PUBMED:7660365 ].
- Sea anemone BgK, a potassium channel toxin [ PUBMED:9020148 ].
- Toxocara canis family of secreted mucins Tc-MUC-1 to -5, which are implicated in immune evasion. They combine two evolutionarily distinct modules, the mucin and ShkT domains [ PUBMED:10950959 , PUBMED:11412804 ].
- Some Caenorhabditis elegans astacin-like proteins (nematode astacins, NAS), metalloproteases [ PUBMED:14653817 ].
- Vertebrate cysteine-rich secretory proteins (Crisp) [ PUBMED:16339766 ].
- Mammalian microfibrillar-associated protein 2 (MFAP2 or MAGP1), a matrix protein.
- Plant prolyl 4-hydroxylase.
Domain organisation
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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Pfam Clan
This family is a member of clan ShK-like (CL0213), which has the following description:
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 [1][2][3].
The clan contains the following 2 members:
Crisp ShKAlignments
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets and the UniProtKB sequence database. More...
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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
| Seed (136) |
Full (10282) |
Representative proteomes | UniProt (18507) |
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| RP15 (6792) |
RP35 (8235) |
RP55 (10716) |
RP75 (11274) |
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| PP/heatmap | 1 | ||||||
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
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We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
| Seed (136) |
Full (10282) |
Representative proteomes | UniProt (18507) |
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|---|---|---|---|---|---|---|---|
| RP15 (6792) |
RP35 (8235) |
RP55 (10716) |
RP75 (11274) |
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| Raw Stockholm | |||||||
| Gzipped | |||||||
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
HMM logo
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
Trees
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
Curation
| Seed source: | Pfam-B_662 (release 4.0) |
| Previous IDs: | DUF18;ShTK; |
| Type: | Domain |
| Sequence Ontology: | SO:0000417 |
| Author: |
Bashton M  , Bateman A
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| Number in seed: | 136 |
| Number in full: | 10282 |
| Average length of the domain: | 36.4 aa |
| Average identity of full alignment: | 29 % |
| Average coverage of the sequence by the domain: | 18.96 % |
HMM information
| HMM build commands: |
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
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| Model details: |
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| Model length: | 37 | ||||||||||||
| Family (HMM) version: | 27 | ||||||||||||
| Download: | download the raw HMM for this family |
Species distribution
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Structures
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 6 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 sequence.
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AlphaFold Structure Predictions
The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.
