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 a rotaxane substructure. The cystine knot motif stabilizes protein structure and is conserved in proteins across various species. There are three types of cystine knot, which differ in the topology of the disulfide bonds:
* The growth factor cystine knot (GFCK)
* inhibitor cystine knot (ICK) common in spider and snail toxins
* Cyclic Cystine Knot, or cyclotide

The growth factor cystine knot was first observed in the structure of nerve growth factor (NGF), solved by X-ray crystallography and published in 1991 by Tom Blundell in Nature.; The GFCK is present in four superfamilies. These include nerve growth factor, transforming growth factor beta (TGF-β), platelet-derived growth factor, and glycoprotein hormones including human chorionic gonadotropin. These are structurally related due to the presence of the cystine knot motif but differ in sequence. All GFCK structures that have been determined are dimeric, but their dimerization modes in different classes are different. The vascular endothelial growth factor subfamily, categorized as part of the platelet-derived growth factor superfamily, includes proteins that are angiogenic factors.

The presence of the cyclic cystine knot (CCK) motif was discovered when cyclotides were isolated from various plant families. The CCK motif has a cyclic backbone, triple stranded beta sheet, and cystine knot conformation.

Novel proteins are being added to the cystine knot motif family, also known as the C-terminal cystine knot (CTCK) proteins. They share approximately 90 amino acid residues in their cysteine-rich C-terminal regions.

Inhibitor cystine knot (ICK) is a structural motif with a triple stranded antiparallel beta sheet linked by three disulfide bonds, forming a knotted core. The ICK motif can be found under the category of phylum, such as animals and plants. It is often found in many venom peptides such as those of snails, spiders, and scorpions. Peptide K-PVIIA, which contains an ICK, can undergo a successful enzymatic backbone cyclization. The disulfide connectivity and the common sequence pattern of the ICK motif provides the stability of the peptides that support cyclization.

Drug implications

The stability and structure of the cystine knot motif implicates possible applications in drug design. The hydrogen bonding between the disulfide bonds of the motif and beta-sheet structures gives rise to highly efficient structure stabilization. In addition, the size of the motif is approximately 30 amino acid residues.Kolmar, Harald. “Biological Diversity and Therapeutic Potential of Natural and Engineered Cystine Knot Miniproteins.” Current Opinion in Pharmacology, vol. 9, no. 5, 2009, pp. 608–614., doi:10.1016/j.coph.2009.05.004. These two characteristics make it an attractive biomolecule to be used for drug delivery as it exhibits thermal stability, chemical stability, and proteolytic resistance. The biological activities of these molecules are partially due to the unique interlocking arrangement and cyclized peptide backbone which contains a conserved sequence shared among circulins. Circulins have previously been identified in a screen for anti-HIV activity.K.R. Gustafson, R.C. Sowder II, L.E. Henderson, I.C. Parsons, Y. Kashman, J.H. Cardellina II, J.B. McMahon, R.W. Buckheit Jr., L.K. Pannell, M.R. Boyd

Circulins A and B: novel HIV-inhibitory macrocyclic peptides from the tropical tree Chassalia parvifolia

J. Am. Chem. Soc., 116 (1994), pp. 9337-9338 Studies have shown that cystine knot proteins can be incubated at temperatures of 65 °C or placed in 1 N HCl/1N NaOH without loss of structural and functional integrity.Craik, David J., et al. “The Cystine Knot Motif in Toxins and Implications for Drug Design.” Toxicon, vol. 39, no. 1, 2001, pp. 43–60., doi:10.1016/s0041-0101(00)00160-4. Its resistance from oral and some intestinal proteases suggest possible use for oral delivery. Possible future applications include pain relief as well as antiviral and antibacterial functions.

References

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Protein structure