Taxonomic distribution of proteins containing ShKT domains

The tree below includes only several representative species and genera. The complete taxonomic breakdown of all proteins containing ShKT domains can be accessed here. Click the counts or percentage values to display the corresponding proteins.

Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms:implications for autoimmune diseases.

Chhabra S, Chang SC, Nguyen HM, Huq R, Tanner MR, Londono LM, Estrada R, Dhawan V, Chauhan S, Upadhyay SK, Gindin M, Hotez PJ, Valenzuela JG, Mohanty B, Swarbrick JD, Wulff H, Iadonato SP, Gutman GA, Beeton C, Pennington MW, Norton RS, Chandy KG
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.

Potassium channel modulation by a toxin domain in matrix metalloprotease23.

Rangaraju S, Khoo KK, Feng ZP, Crossley G, Nugent D, Khaytin I, Chi V, Pham C, Calabresi P, Pennington MW, Norton RS, Chandy KG
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.

A toxin homology domain in an astacin-like metalloproteinase of the jellyfish Podocoryne carnea with a dual role in digestion and development.

Pan T, Groger H, Schmid V, Spring J
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.