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]
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 implicationsedit
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]
Referencesedit
^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.
^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, ISBN9780123878199, retrieved 2019-05-01
^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.
^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.
^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.
^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.
^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.
^ abIyer 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. PMC3328748. PMID 21917115.
^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.
^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. PMC5526200. PMID 27093300.
^ abKolmar, 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.
^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
^ abCraik, 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.
December 15, 2023
cystine, knot, cystine, knot, protein, structural, motif, containing, three, disulfide, bridges, formed, from, pairs, cysteine, residues, sections, polypeptide, that, occur, between, them, form, loop, through, which, third, disulfide, bond, passes, forming, ro. 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 The growth factor cystine knot GFCK inhibitor cystine knot ICK common in spider and snail toxins Cyclic Cystine Knot or cyclotideCystine knot domainStructure of human chorionic gonadotropin 1 IdentifiersSymbolCys knotPfamPF00007Pfam clanCL0079InterProIPR006208SCOP21hcn SCOPe SUPFAMAvailable protein structures Pfam structures ECOD PDBRCSB PDB PDBe PDBjPDBsumstructure summaryPDB1fl7 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 b 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 editThe 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 edit 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 Cystine Knots The Cyclotide Webpage 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 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 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 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 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 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 a b 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 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 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 a b 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 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 a b 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 Retrieved from https en wikipedia org w index php title Cystine knot amp oldid 1171113758, wikipedia, 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