An inhibitor cystine knot (also known as ICK or Knottin) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

structural motif containing three

disulfide bridge In chemistry, a disulfide (or disulphide in British English) is a compound containing a functional group or the anion. The linkage is also called an SS-bond or sometimes a disulfide bridge and usually derived from two thiol groups. In inorg ...

s. Knottins are one of three folds in the cystine knot motif; the other closely related knots are the growth factor cystine knot (GFCK) and the cyclic cystine knot (CCK; cyclotide). Types include a) cyclic mobius, b) cyclic bracelet, c) acyclic inhibitor knottins. Cystine knot motifs are found frequently in nature in a plethora of plants, animals, and fungi and serve diverse functions from appetite suppression to anti-fungal activity. Along with the sections of polypeptide between them, two disulfides form a loop through which the third disulfide bond (linking the 3rd and 6th cysteine in the sequence) passes, forming a

knot A knot is an intentional complication in Rope, cordage which may be practical or decorative, or both. Practical knots are classified by function, including List of hitch knots, hitches, List of bend knots, bends, List of loop knots, loop knots, ...

. The motif is common in invertebrate toxins such as those from

arachnid Arachnids are arthropods in the Class (biology), class Arachnida () of the subphylum Chelicerata. Arachnida includes, among others, spiders, scorpions, ticks, mites, pseudoscorpions, opiliones, harvestmen, Solifugae, camel spiders, Amblypygi, wh ...

s and

molluscs Mollusca is a phylum of protostome, protostomic invertebrate animals, whose members are known as molluscs or mollusks (). Around 76,000 extant taxon, extant species of molluscs are recognized, making it the second-largest animal phylum ...

. The motif is also found in some inhibitor proteins found in plants, but the plant and animal motifs are thought to be a product of

convergent evolution Convergent evolution is the independent evolution of similar features in species of different periods or epochs in time. Convergent evolution creates analogous structures that have similar form or function but were not present in the last comm ...

. The ICK motif is a very stable protein structure which is resistant to heat denaturation and

proteolysis Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Protein degradation is a major regulatory mechanism of gene expression and contributes substantially to shaping mammalian proteomes. Uncatalysed, the hydrolysis o ...

. CK peptide components of venoms target voltage-gated ion channels but members of the family also act as antibacterial and haemolytic agents. Plant ICK proteins are often protease inhibitors. Knottins have high stability to pH, heat, and enzymes. Because of their stability and their favorable pharmacodynamic properties, knottins are becoming increasingly popular as protein engineering scaffolds. Moreover, engineered knottins have shown significant promise as therapeutics, imaging agents, and targeting agents for chemotherapy. The mammalian proteins

Agouti signalling peptide Agouti-signaling protein is a protein that in humans is encoded by the ASIP gene. It is responsible for the distribution of melanin pigment in mammals. Agouti interacts with the melanocortin 1 receptor to determine whether the melanocyte (pigment ...

and Agouti related peptide are the only known mammalian examples of this motif. Both are neuropeptides involved in cell signalling. The former is responsible for hair (fur) colouration. The motif is similar to the cyclic cystine knot or

cyclotide In biochemistry, cyclotides are small, disulfide-rich peptides isolated from plants. Typically containing 28-37 amino acids, they are characterized by their head-to-tail cyclised peptide backbone and the interlocking arrangement of their three ...

, but lacks the cyclisation of the polypeptide backbone which is present in the latter family. The growth factor

cystine knot A cystine knot is a protein structural motif containing three disulfide bridges (formed from pairs of cysteine residues). The sections of polypeptide that occur between two of them form a loop through which a third disulfide bond passes, form ...

(GFCK) is similar to the ICK but its topology is such that it is the bond between the first and fourth disulfide which threads through the loop.

Proteins which contain the ICK motif

* Agouti related peptide *

* Albumin I * Covalitoxin-II * DkTx *

Grammotoxin Grammotoxin is a toxin in the venom of the tarantula '' Grammostola spatulata''. It is a protein toxin that inhibits P-, Q- and N-type voltage-gated calcium channels (Ca 2+ channels) in neurons. Grammotoxin is also known as omega-grammotoxin SI ...

* GsMTx-4 *

Guangxitoxin Guangxitoxin, also known as GxTX, is a peptide toxin found in the venom of the tarantula '' Plesiophrictus guangxiensis''. It primarily inhibits outward voltage-gated Kv2.1 potassium channel currents, which are prominently expressed in pancreati ...

* Hainantoxin *

Hanatoxin Hanatoxin is a toxin found in the venom of the '' Grammostola spatulata'' tarantula. The toxin is mostly known for inhibiting the activation of voltage-gated potassium channels, most specifically Kv4.2 and Kv2.1, by raising its activation thres ...

Heteroscodratoxin-1 Heteroscodratoxin-1 (also known as κ-theraphototoxin-Hm1a, κ-TRTX-Hm1a, δ-theraphotoxin-Hm1a, δ-TRTX-Hm1a, Hm1a or HmTx1) is a neurotoxin produced by the venom glands of '' Heteroscodra maculata'' (Togo starburst tarantula) that shifts the act ...

Huwentoxin Huwentoxins (HWTX) are a group of neurotoxic peptides found in the venom of the Chinese bird spider '' Haplopelma schmidti''. The species was formerly known as ''Haplopelma huwenum'', ''Ornithoctonus huwena'' and ''Selenocosmia huwena''. While str ...

Maurocalcine Maurocalcine (MCa) is a protein, 33 Amino acid residues in length, isolated from the venom of the scorpion '' Maurus palmatus'', which belongs to the family Chactidae, first characterized in 2000. The toxin is present in such small amounts that i ...

* Theraphosa leblondi toxin * δ-Palutoxin *

Phrixotoxin Phrixotoxins are peptide toxins derived from the venom of the Chilean copper tarantula ''Phrixotrichus auratus'', also named ''Paraphysa scrofa''. Phrixotoxin-1 and -2 block A-type voltage-gated potassium channels; phrixotoxin-3 blocks voltage ...

Psalmotoxin Psalmotoxin (PcTx1) is a spider toxin from the venom of the Trinidad tarantula ''Psalmopoeus cambridgei''. It selectively blocks Acid Sensing Ion Channel 1-a (ASIC1a), which is a proton-gated sodium channel. Sources Psalmotoxin is a toxin produ ...

Robustoxin Delta atracotoxin (δ-ACTX-Ar1, robustoxin, or robustotoxin) is a low-molecular mass neurotoxic polypeptide found in the venom of the Sydney funnel-web spider (''Atrax robustus''). Delta atracotoxin produces potentially fatal neurotoxic symptom ...

Stromatoxin Stromatoxin is a spider toxin that blocks certain delayed-rectifier and A-type voltage-gated potassium channels. Etymology Stromatoxin was first identified in the venom of the African tarantula '' Stromatopelma calceatum'' (the featherleg baboon ...

* Tachystatin *

Vanillotoxin Vanillotoxins (VaTxs, subtypes VaTx1, VaTx2, and VaTx3) are neurotoxins found in the venom of the tarantula '' Psalmopoeus cambridgei''. They act as agonists for the transient receptor potential cation channel subfamily V member 1 (TRPV1), activati ...

Vejocalcin Vejocalcin (VjCa, also called Vejocalcine) is a toxin from the venom of the Mexican scorpion '' Vaejovis mexicanus''. Vejocalcin is a member of the calcin family of toxins. It acts as a cell-penetrating peptide (CPP); it binds with high affinity ...

References

{{reflist

External links

The cyclotide webpageThe KNOTTIN Database
Protein structure Neurotoxins Ion channel toxins Protein folds Cysteine-rich proteins