To improve security and privacy, we are moving our web pages and services from HTTP to HTTPS.
To give users of web services time to transition to HTTPS, we will support separate HTTP and HTTPS services until the end of 2017.
From January 2018 most HTTP traffic will be automatically redirected to HTTPS. [more...]
View this page in https
PROSITE documentation PDOC00912 [for PROSITE entry PS01225]

C-terminal cystine knot domain signature and profile


The structures of transforming growth factor-β (TGF-β), nerve growth factor (NGF), platelet-derived growth factor (PDGF) and gonadotropin have been shown to be similar [1,2 and references therein]: these proteins are folded into two highly twisted antiparallel pairs of β-strands and contain three disulfide bonds, of which two form a cystine ring through which the third bond passes (see the schematic representation below). This structure is called cystine knot [3].

            |                 :   :      |
            +--==c====b4===>C-:-C-c-COOH |
                 :          : : :        |
            |                 :
'=>': indicates the direction of the beta-strands 'b1' to 'b4'.
'C' : conserved cysteine in cystine knot.
'c' : additional conserved cysteine in C-terminal cystine knot.
':' : disulfide bridge.

Functional diverse modular proteins share a conserved domain of about 90 amino acids in their C-terminal cysteine-rich region, that has been proposed [4,5] to be structurally related to the cystine-knot family [3] and which is therefore called C-terminal cystine-knot (CTCK). Members of the C-terminal cystine knot family are listed below:

  • von Willebrand factor (vWF), a multifunctional protein which is involved in maintaining homeostasis. It consists of 4 vWF type D domains, 3 vWF type A domains, 3 vWF type B domains, 2 vWF type C domains (see <PDOC00928>, a X domain and the C-terminal cystine knot.
  • Mucins. Human mucin 2, a highly polymorphic multidomain molecule with a modular architecture similar to vWF. Xenopus mucin B.1 which contains a CCP domain, a vWF type C domain, a X domain and a CTCK. Other mucins that contain a CTCK are the human tracheobronchial mucin (gene MUC5), bovine submaxillary mucin-like protein, pig apomucin and rat intestinal mucin-like protein.
  • CCN family (cef-10/cyr61/CTFG/fisp-12/nov protein family). These growth- factor inducible proteins are structurally related to the insulin-like growth factor binding proteins (see <PDOC00194>) and could also function as growth-factor binding proteins.
  • Drosophila slit protein which is essential for development of midline glia and commissural axon pathways. It is composed of four leucine-rich repeats, seven EGF-like domains, a laminin G-like repeat and the CTCK.
  • Norrie disease protein (NDP) which may be involved in neuroectodermal cell- cell interaction and in a pathway that regulates neural cell differentiation and proliferation.
  • Silk moth hemocytin, an humoral lectin which is involved in a self-defence mechanism. It is composed of 2 FA58C domains (see <PDOC00988>), a C-type lectin domain (see <PDOC00537>), 2 VWFC domains (see <PDOC00928), and a CTCK.

The pattern we developed for CTCK correspond to the C-terminal half of the domain.

Expert(s) to contact by email:

Bork P.

Last update:

May 2004 / Text revised.

Technical section

PROSITE methods (with tools and information) covered by this documentation:

CTCK_2, PS01225; C-terminal cystine knot domain profile  (MATRIX)

CTCK_1, PS01185; C-terminal cystine knot signature  (PATTERN)


1AuthorsIsaaks N.W.
SourceCurr. Opin. Struct. Biol. 5:391-395(1995).

2AuthorsSun P.D., Davies D.R.
TitleThe cystine-knot growth-factor superfamily.
SourceAnnu. Rev. Biophys. Biomol. Struct. 24:269-291(1995).
PubMed ID7663117

3AuthorsMcDonald N.Q., Hendrickson W.A.
TitleA structural superfamily of growth factors containing a cystine knot motif.
SourceCell 73:421-424(1993).
PubMed ID8490958

4AuthorsMeitinger T., Meindl A., Bork P., Rost B., Sander C., Haasemann M., Murken J.
TitleMolecular modelling of the Norrie disease protein predicts a cystine knot growth factor tertiary structure.
SourceNat. Genet. 5:376-380(1993).
PubMed ID8298646

5AuthorsBork P.
TitleThe modular architecture of a new family of growth regulators related to connective tissue growth factor.
SourceFEBS Lett. 327:125-130(1993).
PubMed ID7687569

PROSITE is copyright. It is produced by the SIB Swiss Institute Bioinformatics. There are no restrictions on its use by non-profit institutions as long as its content is in no way modified. Usage by and for commercial entities requires a license agreement. For information about the licensing scheme send an email to
Prosite License or see: prosite_license.html.


View entry in original PROSITE document format
View entry in raw text format (no links)