An inhibitor cystine knot (aka ICK or Knottin) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

structural motif containing three

disulfide bridge In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...

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 cordage which may be practical or decorative, or both. Practical knots are classified by function, including hitches, bends, loop knots, and splices: a ''hitch'' fastens a rope to another object; a ' ...

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

arachnid Arachnida () is a class of joint-legged invertebrate animals (arthropods), in the subphylum Chelicerata. Arachnida includes, among others, spiders, scorpions, ticks, mites, pseudoscorpions, harvestmen, camel spiders, whip spiders and vinegaroon ...

s and

molluscs Mollusca is the second-largest phylum of invertebrate animals after the Arthropoda, the members of which are known as molluscs or mollusks (). Around 85,000 extant taxon, extant species of molluscs are recognized. The number of fossil sp ...

. 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 com ...

. 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. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called protease ...

. 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, forming ...

(GFCK) shares the motif 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 S ...

* GsMTx-4 * Guangxitoxin * 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 * Huwentoxin * Maurocalcine * Theraphosa leblondi toxin * δ-Palutoxin * Phrixotoxin * Psalmotoxin *

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

* Stromatoxin * 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

References

{{reflist

External links

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