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35  structures 324  species 0  interactions 3503  sequences 46  architectures

Family: Cys_knot (PF00007)

Summary: Cystine-knot domain

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This is the Wikipedia entry entitled "Cystine knot". More...

Cystine knot Edit Wikipedia article

Cystine-knot domain
PDB 1hcn EBI.jpg
Structure of human chorionic gonadotropin.[1]
Pfam clanCL0079

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) was first observed in the structure of Nerve Growth Factor, solved by X-ray crystallography and published in 1991 by Tom Blundell in Nature.[6] 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.[7] All GFCK structures that have been determined are dimeric, but their dimerization modes in different classes are different.[8]

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]

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.[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. 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. [11]


  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.
  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/ 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. ^ 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.
  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.

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

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.

Literature references

  1. Bork P; , FEBS Lett 1993;327:125-130.: The modular architecture of a new family of growth regulators related to connective tissue growth factor. PUBMED:7687569 EPMC:7687569

Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR006208

This domain is found at the C-terminal of glycoprotein hormones and various extracellular proteins. It is believed to be involved in disulphide-linked dimerisation [ PUBMED:7687569 ].

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan Cystine-knot (CL0079), which has the following description:

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


We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets and the UniProtKB sequence database. More...

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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.

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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

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HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...


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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Curation and family details

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.

Curation View help on the curation process

Seed source: Published_alignment enriched with PDOC00234 members.
Previous IDs: none
Type: Domain
Sequence Ontology: SO:0000417
Author: Sonnhammer ELL
Number in seed: 24
Number in full: 3503
Average length of the domain: 95.70 aa
Average identity of full alignment: 26 %
Average coverage of the sequence by the domain: 33.75 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 57096847 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 21.3 21.3
Trusted cut-off 21.3 21.3
Noise cut-off 21.2 21.2
Model length: 105
Family (HMM) version: 24
Download: download the raw HMM for this family

Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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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 35 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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AlphaFold Structure Predictions

The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.

Protein Predicted structure External Information
A0A0R4IXA2 View 3D Structure Click here
A0A2R8QBQ7 View 3D Structure Click here
A0A2R8QL03 View 3D Structure Click here
A0A2R8QSD5 View 3D Structure Click here
A0A6I8WFJ4 View 3D Structure Click here
A5PN60 View 3D Structure Click here
A6NKQ9 View 3D Structure Click here
A7DT38 View 3D Structure Click here
B3DJU0 View 3D Structure Click here
C6SUS4 View 3D Structure Click here
D0E2W2 View 3D Structure Click here
D3Z5L9 View 3D Structure Click here
D3ZDL5 View 3D Structure Click here
D3ZEP2 View 3D Structure Click here
F1Q5N9 View 3D Structure Click here
F1QG76 View 3D Structure Click here
F1QL10 View 3D Structure Click here
F1QYF3 View 3D Structure Click here
F1R8E6 View 3D Structure Click here
O00622 View 3D Structure Click here
O09108 View 3D Structure Click here
O54775 View 3D Structure Click here
O95388 View 3D Structure Click here
O95389 View 3D Structure Click here
P01222 View 3D Structure Click here
P01225 View 3D Structure Click here
P01229 View 3D Structure Click here
P01230 View 3D Structure Click here
P04652 View 3D Structure Click here
P0DN86 View 3D Structure Click here
P0DN87 View 3D Structure Click here
P12656 View 3D Structure Click here
P18406 View 3D Structure Click here
P18427 View 3D Structure Click here
P29268 View 3D Structure Click here
P29279 View 3D Structure Click here
P48744 View 3D Structure Click here
P48745 View 3D Structure Click here
P98089 View 3D Structure Click here
Q00604 View 3D Structure Click here
Q4V4C8 View 3D Structure Click here
Q5RI33 View 3D Structure Click here
Q5VJF5 View 3D Structure Click here
Q60687 View 3D Structure Click here
Q64299 View 3D Structure Click here
Q6NT52 View 3D Structure Click here
Q6TCF5 View 3D Structure Click here
Q6TCF7 View 3D Structure Click here
Q812B2 View 3D Structure Click here
Q86YW7 View 3D Structure Click here
Q99PP0 View 3D Structure Click here
Q9ES72 View 3D Structure Click here
Q9QZQ5 View 3D Structure Click here
Q9R1E9 View 3D Structure Click here