The domain within your query sequence starts at position 255 and ends at position 291; the E-value for the ShKT domain shown below is 4.06e-10.

GCLDRIFVCASWARKGFCDVRQRLMKRLCPRSCDFCY

ShKT

ShK toxin domain

• SMART accession number: SM00254
• Description: ShK toxin domain
• Interpro abstract (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.

There are 13829 ShKT domains in 7329 proteins in SMART's nrdb database.

Literature (relevant references for this domain)

Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

• Chhabra S et al.
• Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms:implications for autoimmune diseases.
• FASEB J. 2014; 0: 0-0

The voltage-gated potassium (Kv) 1.3 channel is widely regarded as a therapeutic target for immunomodulation in autoimmune diseases. ShK-186, a selectiveinhibitor of Kv1.3 channels, ameliorates autoimmune diseases in rodent models,and human phase 1 trials of this agent in healthy volunteers have been completed.In this study, we identified and characterized a large family of Stichodactylahelianthus toxin (ShK)-related peptides in parasitic worms. Based on phylogeneticanalysis, 2 worm peptides were selected for study: AcK1, a 51-residue peptideexpressed in the anterior secretory glands of the dog-infecting hookwormAncylostoma caninum and the human-infecting hookworm Ancylostoma ceylanicum, and BmK1, the C-terminal domain of a metalloprotease from the filarial worm Brugiamalayi. These peptides in solution adopt helical structures closely resemblingthat of ShK. At doses in the nanomolar-micromolar range, they block native Kv1.3 in human T cells and cloned Kv1.3 stably expressed in L929 mouse fibroblasts.They preferentially suppress the proliferation of rat CCR7- effector memory Tcells without affecting naive and central memory subsets and inhibit thedelayed-type hypersensitivity (DTH) response caused by skin-homing effectormemory T cells in rats. Further, they suppress IFNgamma production by human Tlymphocytes. ShK-related peptides in parasitic worms may contribute to thepotential beneficial effects of probiotic parasitic worm therapy in humanautoimmune diseases.-Chhabra, S., Chang, S. C., Nguyen, H. M., Huq, R., Tanner,M. R., Londono, L. M., Estrada, R., Dhawan, V., Chauhan, S., Upadhyay, S. K.,Gindin, M., Hotez, P. J., Valenzuela, J. G., Mohanty, B., Swarbrick, J. D.,Wulff, H., Iadonato, S. P., Gutman, G. A., Beeton, C., Pennington, M. W., Norton,R. S., Chandy, K. G. Kv1.3 channel-blocking immunomodulatory peptides fromparasitic worms: implications for autoimmune diseases.

• Rangaraju S et al.
• Potassium channel modulation by a toxin domain in matrix metalloprotease23.
• J Biol Chem. 2010; 285: 9124-36

Peptide toxins found in a wide array of venoms block K(+) channels,causing profound physiological and pathological effects. Here we describethe first functional K(+) channel-blocking toxin domain in a mammalianprotein. MMP23 (matrix metalloprotease 23) contains a domain (MMP23(TxD))that is evolutionarily related to peptide toxins from sea anemones.MMP23(TxD) shows close structural similarity to the sea anemone toxins BgKand ShK. Moreover, this domain blocks K(+) channels in the nanomolar tolow micromolar range (Kv1.6 > Kv1.3 > Kv1.1 = Kv3.2 > Kv1.4, in decreasingorder of potency) while sparing other K(+) channels (Kv1.2, Kv1.5, Kv1.7,and KCa3.1). Full-length MMP23 suppresses K(+) channels by co-localizingwith and trapping MMP23(TxD)-sensitive channels in the ER. Our resultsprovide clues to the structure and function of the vast family of proteinsthat contain domains related to sea anemone toxins. Evolutionary pressureto maintain a channel-modulatory function may contribute to theconservation of this domain throughout the plant and animal kingdoms.

• Pan T, Groger H, Schmid V, Spring J
• A toxin homology domain in an astacin-like metalloproteinase of the jellyfish Podocoryne carnea with a dual role in digestion and development.
• Dev Genes Evol. 1998; 208: 259-66

Metalloproteinases of the astacin family such as tolloid play major roles in animal morphogenesis. Cnidarians are thought to be evolutionary simple organisms and, therefore, a metalloproteinase from the marine hydrozoan Podocoryne carnea was analysed to evaluate the role of this conserved gene familiy at the base of animal evolution. Surprisingly, the proteinase domain of Podocornyne PMP1 is more similar to human meprin than to HMP1 from another hydrozoan, the freshwater polyp Hydra vulgaris. However, PMP1 and HMP1 both contain a small C-terminal domain with six cysteines that distinguishes them from other astacin-like molecules. Similar domains have been described only recently from sea anemone toxins specific for potassium channels. This toxin homology (Tox1) domain is clearly distinct from epidermal growth factor (EGF)-like domains or other cysteine-rich modules and terminates with the characteristic pattern CXXXCXXC with three out of six cysteines in the last eight residues of the protein. PMP1 is transiently expressed at various sites of morphogenetic activity during medusa bud development. In the adult medusa, however, expression is concentrated to the manubrium, the feeding organ, where the PMP1 gene is highly induced upon feeding. These disparate expression patterns suggest a dual role of PMP1 comparable to tolloid in development and, like astacin in the crayfish, also for food digestion. The Tox1 domain of PMP1 could serve as a toxin to keep the pray paralysed after ingestion, but as a sequence module such Tox1 domains with six cysteines are neither restricted to cnidarians nor to toxins.

Metabolism (metabolic pathways involving proteins which contain this domain)

% proteins involved	KEGG pathway ID	Description
20.00	map00350	Tyrosine metabolism
20.00	map04916	Melanogenesis
20.00	map00740	Riboflavin metabolism
20.00	map00330	Arginine and proline metabolism
20.00	map00950	Alkaloid biosynthesis I

This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with ShKT domain which could be assigned to a KEGG orthologous group, and not all proteins containing ShKT domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

Structure (3D structures containing this domain)

3D Structures of ShKT domains in PDB

PDB code	Title
1bei	SHK-DNP22: A POTENT KV1.3-SPECIFIC IMMUNOSUPPRESSIVE POLYPEPTIDE, NMR, 20 STRUCTURES
1rc9	Crystal Structure of Stecrisp, a Member of CRISP Family from Trimeresurus Stejnegeri Refined at 1.6 Angstroms Resolution: Structual relationship of the two domains
1roo	NMR SOLUTION STRUCTURE OF SHK TOXIN, NMR, 20 STRUCTURES
1wvr	Crystal Structure of a CRISP family Ca-channel blocker derived from snake venom
1xta	Crystal Structure of Natrin, a snake venom CRISP from Taiwan cobra (Naja atra)
1xx5	Crystal Structure of Natrin from Naja atra snake venom
2giz	Structural and functional analysis of Natrin, a member of crisp-3 family blocks a variety of ion channels
2k72	Solution NMR structure of toxin-like potassium channel blocking domain in MMP23
2k9e	NMR Solution Structure for ShK-192: A Potent KV1.3-Specific Immunosuppressive Polypeptide
2lg4	3D solution structure of antimicrobial peptide aurelin
2mcr	2MCR
3mz8	Crystal Structure of Zinc-Bound Natrin From Naja atra
4lfq	High resolution x-ray crystal structure of L-ShK toxin
4lfs	High resolution x-ray structure of racemic ShK toxin

Links (links to other resources describing this domain)

• INTERPRO: IPR003582