Summary: Cystine-knot domain
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Cystine knot Edit Wikipedia article
Structure of human chorionic gonadotropin.
|SCOPe||1hcn / SUPFAM|
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 (GFCK) was first observed in the structure of Nerve Growth Factor, solved by X-ray crystallography and published in 1991 by Tom Blundell in Nature. The GFCK comprises four superfamilies. These include nerve growth factor, transforming growth factor beta, 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.
There are currently novel proteins being added to the cystine knot motif family, which are called 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. ICK motif can be found under the category of phylum, such as animals and plants. It is usually found in many venom peptides, which is in the venoms of snails, spiders, and scorpions. Peptide K-PVIIA that contains an ICK can undergo a successful enzymatic backbone cyclization. The disulfide connectivity and the common sequence pattern of ICK motif provide the stability of the peptides that supports cyclization. 
- 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): 545â€“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. 3â€“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): 681â€“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): 362â€“8. doi:10.1016/j.cbpa.2011.02.008. PMID 21362584.
- Bibcode:1991Natur.354..411M. doi:10.1038/354411a0. PMID 1956407. ; 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): 411â€“4.
- Sun PD, Davies DR (1995). "The cystine-knot growth-factor superfamily". Annual Review of Biophysics and Biomolecular Structure. 24 (1): 269â€“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): 424â€“451. doi:10.1016/j.mce.2013.08.021. PMID 24001578.
- 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): 4304â€“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): 1327â€“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 knotâ€containing peptide". Biotechnology and Bioengineering. 113 (10): 2202â€“2212. doi:10.1002/bit.25993. PMC 5526200. PMID 27093300.
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Cystine-knot domain Provide feedback
The family comprises glycoprotein hormones and the C-terminal domain of various extracellular proteins. It is believed to be involved in disulfide-linked dimerisation.
Internal database links
|SCOOP:||DAN Hormone_6 Sclerostin|
External database links
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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The cytokine families in this clan have the cystine-knot fold. In this 6 cysteines form three disulphide bridges that are interlinked.
The clan contains the following 14 members:Coagulin Cys_knot Cys_Knot_tox D_CNTX DAN Hormone_6 IL17 m_DGTX_Dc1a_b_c NGF Noggin PDGF Sclerostin Spaetzle TGF_beta
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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
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This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Seed source:||Published_alignment enriched with PDOC00234 members.|
|Number in seed:||24|
|Number in full:||2919|
|Average length of the domain:||96.00 aa|
|Average identity of full alignment:||26 %|
|Average coverage of the sequence by the domain:||34.65 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 47079205 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||23|
|Download:||download the raw HMM for this family|
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How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
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Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
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For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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There are 6 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Cys_knot domain has been found. There are 33 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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