Summary: ShK domain-like
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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 688 proteins, most of them from C. elegans (InterPro: IPR003582). The SMART database at the EMBL has a list of 688 proteins containing 1315 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).
ShK toxin blocks the K+ channels Kv1.1, Kv1.3, Kv1.6, Kv3.2 and KCa3.1, 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  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-diastereomer 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. ShK-K-amide is a new analog with a C-terminal lysine. It blocks Kv1.3 with roughly 50-fold greater potency (IC50 of 26 ± 3 pM) than Kv1.1 ( IC50 of 942 ± 120 pM), and suppresses proliferation of human T cells (IC50 ≈ 3 nM).
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. ShK-186 is the subject of an open Investigational New Drug (IND) application in the USA, and has completed human phase 1A and 1B trials in healthy volunteers.
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. ShK-186 (aka Dalazatide) which was licensed to Kineta Bio is the subject of an open Investigational New Drug (IND) application in the United States of America, and has recently completed human phase 1A and 1b trials in healthy volunteers. A second human phase 1b was recently completed in 2015 in psoriasis patients. Dalazatide was shown to significantly ameliorate symptoms in 90% patients with active plaque psoriasis with a 60 mcg weekly dose.
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.
- doi:10.1038/nsb0496-317. PMID 8599755.; 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.
- 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, Pennington MW (1995). "Assignment of the three disulfide bonds in ShK toxin: A potent potassium channel inhibitor from the sea anemone Stichodactyla helianthus" (PDF). 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. PMC . 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. PMC . PMID 11585781.
- Kalman K, Pennington MW, Lanigan MD, Nguyen A, Rauer H, Mahnir V, Paschetto K, Kem WR, Grissmer S, Gutman GA, Christian EP, Cahalan MD, Norton RS, Chandy KG (December 1998). "ShK-Dap22, a potent Kv1.3-specific immunosuppressive polypeptide". J. Biol. Chem. 273 (49): 32697–707. doi:10.1074/jbc.273.49.32697. PMID 9830012.
- Rauer H, Pennington M, Cahalan M, Chandy KG (July 1999). "Structural conservation of the pores of calcium-activated and voltage-gated potassium channels determined by a sea anemone toxin". J. Biol. Chem. 274 (31): 21885–92. doi:10.1074/jbc.274.31.21885. PMID 10419508.
- Middleton RE, Sanchez M, Linde AR, Bugianesi RM, Dai G, Felix JP, Koprak SL, Staruch MJ, Bruguera M, Cox R, Ghosh A, Hwang J, Jones S, Kohler M, Slaughter RS, McManus OB, Kaczorowski GJ, Garcia ML (November 2003). "Substitution of a single residue in Stichodactyla helianthus peptide, ShK-Dap22, reveals a novel pharmacological profile". Biochemistry. 42 (46): 13698–707. doi:10.1021/bi035209e. PMID 14622016.
- Beeton C, Pennington MW, Wulff H, Singh S, Nugent D, Crossley G, Khaytin I, Calabresi PA, Chen CY, Gutman GA, Chandy KG (April 2005). "Targeting effector memory T cells with a selective peptide inhibitor of Kv1.3 channels for therapy of autoimmune diseases". Mol. Pharmacol. 67 (4): 1369–81. doi:10.1124/mol.104.008193. PMID 15665253.
- Yan L, Herrington J, Goldberg E, Dulski PM, Bugianesi RM, Slaughter RS, Banerjee P, Brochu RM, Priest BT, Kaczorowski GJ, Rudy B, Garcia ML (May 2005). "Stichodactyla helianthus peptide, a pharmacological tool for studying Kv3.2 channels". Mol. Pharmacol. 67 (5): 1513–21. doi:10.1124/mol.105.011064. PMID 15709110.
- Lanigan MD, Kalman K, Lefievre Y, Pennington MW, Chandy KG, Norton RS (October 2002). "Mutating a critical lysine in ShK toxin alters its binding configuration in the pore-vestibule region of the voltage-gated potassium channel, Kv1.3". Biochemistry. 41 (40): 11963–71. doi:10.1021/bi026400b. PMID 12356296.
- Chandy KG, Wulff H, Beeton C, Pennington M, Gutman GA, Cahalan MD (May 2004). "K+ channels as targets for specific immunomodulation". Trends Pharmacol. Sci. 25 (5): 280–9. doi:10.1016/j.tips.2004.03.010. PMC . PMID 15120495.
- Norton RS, Pennington MW, Wulff H (December 2004). "Potassium channel blockade by the sea anemone toxin ShK for the treatment of multiple sclerosis and othfer autoimmune diseases". Curr. Med. Chem. 11 (23): 3041–52. doi:10.2174/0929867043363947. PMID 15578998.
- Beeton C, Wulff H, Singh S, Botsko S, Crossley G, Gutman GA, Cahalan MD, Pennington M, Chandy KG (March 2003). "A novel fluorescent toxin to detect and investigate Kv1.3 channel up-regulation in chronically activated T lymphocytes". J. Biol. Chem. 278 (11): 9928–37. doi:10.1074/jbc.M212868200. PMID 12511563.
- Beeton C, Wulff H, Standifer NE, Azam P, Mullen KM, Pennington MW, Kolski-Andreaco A, Wei E, Grino A, Counts DR, Wang PH, LeeHealey CJ, S Andrews B, Sankaranarayanan A, Homerick D, Roeck WW, Tehranzadeh J, Stanhope KL, Zimin P, Havel PJ, Griffey S, Knaus HG, Nepom GT, Gutman GA, Calabresi PA, Chandy KG (November 2006). "Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases". Proc. Natl. Acad. Sci. U.S.A. 103 (46): 17414–9. doi:10.1073/pnas.0605136103. PMC . PMID 17088564.
- Pennington MW, Beeton C, Galea CA, Smith BJ, Chi V, Monaghan KP, Garcia A, Rangaraju S, Giuffrida A, Plank D, Crossley G, Nugent D, Khaytin I, Lefievre Y, Peshenko I, Dixon C, Chauhan S, Orzel A, Inoue T, Hu X, Moore RV, Norton RS, Chandy KG (January 2009). "Engineering a stable and selective peptide blocker of the Kv1.3 channel in T lymphocytes". Mol. Pharmacol. 75 (4): 762–73. doi:10.1124/mol.108.052704. PMC . PMID 19122005.
- 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 (3): 642–653. doi:10.1124/jpet.112.191890. PMID 22637724.
- Beeton C, Smith BJ, Sabo JK, Crossley G, Nugent D, Khaytin I, Chi V, Chandy KG, Pennington MW, Norton RS (January 2008). "The D-diastereomer of ShK toxin selectively blocks voltage-gated K+ channels and inhibits T lymphocyte proliferation". J. Biol. Chem. 283 (2): 988–97. doi:10.1074/jbc.M706008200. PMID 17984097.
- Pennington MW, Rashid MH, Tajhya RB, Beeton C, Kuyucak S, Norton RS (November 2012). "A C-terminally amidated analogue of ShK is a potent and selective blocker of the voltage-gated potassium channel Kv1.3". FEBS Lett. 586 (22): 3996–4001. doi:10.1016/j.febslet.2012.09.038. PMC . PMID 23063513.
- Wulff H, Calabresi PA, Allie R, Yun S, Pennington M, Beeton C, Chandy KG (June 2003). "The voltage-gated Kv1.3 K+ channel in effector memory T cells as new target for MS". J. Clin. Invest. 111 (11): 1703–13. doi:10.1172/JCI16921. PMC . PMID 12782673.
- Matheu MP, Beeton C, Garcia A, Chi V, Rangaraju S, Safrina O, Monaghan K, Uemura MI, Li D, Pal S, de la Maza LM, Monuki E, Flügel A, Pennington MW, Parker I, Chandy KG, Cahalan MD (October 2008). "Imaging of effector memory T cells during a delayed-type hypersensitivity reaction and suppression by Kv1.3 channel block". Immunity. 29 (4): 602–14. doi:10.1016/j.immuni.2008.07.015. PMC . PMID 18835197.
- Beeton C, Wulff H, Barbaria J, Clot-Faybesse O, Pennington M, Bernard D, Cahalan MD, Chandy KG, Béraud E (November 2001). "Selective blockade of T lymphocyte K+ channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis". Proc. Natl. Acad. Sci. U.S.A. 98 (24): 13942–7. doi:10.1073/pnas.241497298. PMC . PMID 11717451.
- Wulff H, Beeton C, Chandy KG (September 2003). "Potassium channels as therapeutic targets for autoimmune disorders". Curr Opin Drug Discov Devel. 6 (5): 640–7. PMID 14579513.
- Tucker K, Overton JM, Fadool DA (August 2008). "Kv1.3 gene-targeted deletion alters longevity and reduces adiposity by increasing locomotion and metabolism in melanocortin-4 receptor-null mice". Int J Obes (Lond). 32 (8): 1222–32. doi:10.1038/ijo.2008.77. PMC . PMID 18542083.
- Xu J, Koni PA, Wang P, Li G, Kaczmarek L, Wu Y, Li Y, Flavell RA, Desir GV (March 2003). "The voltage-gated potassium channel Kv1.3 regulates energy homeostasis and body weight". Hum. Mol. Genet. 12 (5): 551–9. doi:10.1093/hmg/ddg049. PMID 12588802.
- Xu J, Wang P, Li Y, Li G, Kaczmarek LK, Wu Y, Koni PA, Flavell RA, Desir GV (March 2004). "The voltage-gated potassium channel Kv1.3 regulates peripheral insulin sensitivity". Proc. Natl. Acad. Sci. U.S.A. 101 (9): 3112–7. doi:10.1073/pnas.0308450100. PMC . PMID 14981264.
- Valverde P, Kawai T, Taubman MA (June 2005). "Potassium channel-blockers as therapeutic agents to interfere with bone resorption of periodontal disease". J. Dent. Res. 84 (6): 488–99. doi:10.1177/154405910508400603. PMID 15914584.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
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
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) ressembling 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 serines protaeses 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.
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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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
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, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the UniProtKB sequence database using the family HMM
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
- an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
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.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
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.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
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...
If you find these logos useful in your own work, please consider citing the following article:
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.
|Seed source:||Pfam-B_662 (release 4.0)|
|Author:||Bashton M, Bateman A|
|Number in seed:||140|
|Number in full:||7196|
|Average length of the domain:||36.30 aa|
|Average identity of full alignment:||28 %|
|Average coverage of the sequence by the domain:||20.41 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||23|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
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 5 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.
Loading structure mapping...