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.[2][3][4] There are three types of cystine knot, which differ in the topology of the disulfide bonds:[5]

Cystine-knot domain
Structure of human chorionic gonadotropin.[1]
Identifiers
SymbolCys_knot
PfamPF00007
Pfam clanCL0079
InterProIPR006208
SCOP21hcn / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB1fl7​, 1hcn​, 1hrp​, 1qfw​, 1xwd​

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.[6] 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.[7] All GFCK structures that have been determined are dimeric, but their dimerization modes in different classes are different.[8] The vascular endothelial growth factor subfamily, categorized as part of the platelet-derived growth factor superfamily, includes proteins that are angiogenic factors.[9]

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.[10]

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.[9]

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. [11]

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.[12] 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.[12] Circulins have previously been identified in a screen for anti-HIV activity.[13] Studies have shown that cystine knot proteins can be incubated at temperatures of 65 °C or placed in 1N HCl/1N NaOH without loss of structural and functional integrity.[14] 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.[14]

References
  1. Wu H, Lustbader JW, Liu Y, Canfield RE, Hendrickson WA (June 1994). "Structure of human chorionic gonadotropin at 2.6 A resolution from MAD analysis of the selenomethionyl protein". Structure. 2 (6): 545–58. doi:10.1016/s0969-2126(00)00054-x. PMID 7922031.
  2. "Cystine Knots". The Cyclotide Webpage.
  3. Sherbet, G.V. (2011), "Growth Factor Families", Growth Factors and Their Receptors in Cell Differentiation, Cancer and Cancer Therapy, Elsevier, pp. 3–5, doi:10.1016/b978-0-12-387819-9.00002-5, ISBN 9780123878199, retrieved 2019-05-01
  4. Vitt, Ursula A.; Hsu, Sheau Y.; Hsueh, Aaron J. W. (2001-05-01). "Evolution and Classification of Cystine Knot-Containing Hormones and Related Extracellular Signaling Molecules". Molecular Endocrinology. 15 (5): 681–694. doi:10.1210/mend.15.5.0639. ISSN 0888-8809. PMID 11328851.
  5. Daly NL, Craik DJ (June 2011). "Bioactive cystine knot proteins". Current Opinion in Chemical Biology. 15 (3): 362–8. doi:10.1016/j.cbpa.2011.02.008. PMID 21362584.
  6. PDB: 1bet​; McDonald NQ, Lapatto R, Murray-Rust J, Gunning J, Wlodawer A, Blundell TL (December 1991). "New protein fold revealed by a 2.3-A resolution crystal structure of nerve growth factor". Nature. 354 (6352): 411–4. Bibcode:1991Natur.354..411M. doi:10.1038/354411a0. PMID 1956407. S2CID 4346788.
  7. Sun PD, Davies DR (1995). "The cystine-knot growth-factor superfamily". Annual Review of Biophysics and Biomolecular Structure. 24 (1): 269–91. doi:10.1146/annurev.bb.24.060195.001413. PMID 7663117.
  8. Jiang X, Dias JA, He X (January 2014). "Structural biology of glycoprotein hormones and their receptors: insights to signaling". Molecular and Cellular Endocrinology. 382 (1): 424–451. doi:10.1016/j.mce.2013.08.021. PMID 24001578.
  9. Iyer S, Acharya KR (November 2011). "Tying the knot: the cystine signature and molecular-recognition processes of the vascular endothelial growth factor family of angiogenic cytokines". The FEBS Journal. 278 (22): 4304–22. doi:10.1111/j.1742-4658.2011.08350.x. PMC 3328748. PMID 21917115.
  10. Craik DJ, Daly NL, Bond T, Waine C (December 1999). "Plant cyclotides: A unique family of cyclic and knotted proteins that defines the cyclic cystine knot structural motif". Journal of Molecular Biology. 294 (5): 1327–36. doi:10.1006/jmbi.1999.3383. PMID 10600388.
  11. Kwon, Soohyun; Bosmans, Frank; Kaas, Quentin; Cheneval, Oliver; Cinibear, Anne C; Rosengren, K Johan; Wang, Conan K; Schroeder, Christina I; Craik, David J (19 April 2016). "Efficient enzymatic cyclization of an inhibitory cystine knot‐containing peptide". Biotechnology and Bioengineering. 113 (10): 2202–2212. doi:10.1002/bit.25993. PMC 5526200. PMID 27093300.
  12. 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.
  13. 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
  14. 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.
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