PROSITE documentation PDOC00912
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

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