PROSITE documentation PDOC00912C-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].
+--<======b3======C---c------+ | : : | +--==c====b4===>C-:-C-c-COOH | : : : : | +--==c====b2===>C---C--------+ | : +--<======b1======C--------------NH(2)
'=>': 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: Last update:May 2004 / Text revised.
-------------------------------------------------------------------------------
PROSITE methods (with tools and information) covered by this documentation:
1 | Authors | Isaaks N.W. |
Source | Curr. Opin. Struct. Biol. 5:391-395(1995). |
2 | Authors | Sun P.D. Davies D.R. |
Title | The cystine-knot growth-factor superfamily. | |
Source | Annu. Rev. Biophys. Biomol. Struct. 24:269-291(1995). | |
PubMed ID | 7663117 |
3 | Authors | McDonald N.Q. Hendrickson W.A. |
Title | A structural superfamily of growth factors containing a cystine knot motif. | |
Source | Cell 73:421-424(1993). | |
PubMed ID | 8490958 |
4 | Authors | Meitinger T. Meindl A. Bork P. Rost B. Sander C. Haasemann M. Murken J. |
Title | Molecular modelling of the Norrie disease protein predicts a cystine knot growth factor tertiary structure. | |
Source | Nat. Genet. 5:376-380(1993). | |
PubMed ID | 8298646 | |
DOI | 10.1038/ng1293-376 |
5 | Authors | Bork P. |
Title | The modular architecture of a new family of growth regulators related to connective tissue growth factor. | |
Source | FEBS Lett. 327:125-130(1993). | |
PubMed ID | 7687569 |
PROSITE is copyrighted by the SIB Swiss Institute of Bioinformatics and distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND 4.0) License, see prosite_license.html.
View entry in original PROSITE document format
View entry in raw text format (no links)