{PDOC00912}
{PS01185; CTCK_1}
{PS01225; CTCK_2}
{BEGIN}
********************************************************
* C-terminal cystine knot domain signature and profile *
********************************************************

The structures  of  transforming  growth  factor-beta (TGF-beta), 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 beta-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.

-Consensus pattern: C-C-x(13)-C-x(2)-[GN]-x(12)-C-x-C-x(2,4)-C
                    [The 6 C's are involved in disulfide bonds]
-Sequences known to belong to this class detected by the pattern: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.

-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.

-Expert(s) to contact by email:
           Bork P.; bork@embl-heidelberg.de

-Last update: May 2004 / Text revised.

[ 1] Isaaks N.W.
     Curr. Opin. Struct. Biol. 5:391-395(1995).
[ 2] Sun P.D., Davies D.R.
     "The cystine-knot growth-factor superfamily."
     Annu. Rev. Biophys. Biomol. Struct. 24:269-291(1995).
     PubMed=7663117
[ 3] McDonald N.Q., Hendrickson W.A.
     "A structural superfamily of growth factors containing a cystine knot
     motif."
     Cell 73:421-424(1993).
     PubMed=8490958
[ 4] Meitinger T., Meindl A., Bork P., Rost B., Sander C., Haasemann M.,
     Murken J.
     "Molecular modelling of the Norrie disease protein predicts a cystine
     knot growth factor tertiary structure."
     Nat. Genet. 5:376-380(1993).
     PubMed=8298646; DOI=10.1038/ng1293-376
[ 5] Bork P.
     "The modular architecture of a new family of growth regulators related
     to connective tissue growth factor."
     FEBS Lett. 327:125-130(1993).
     PubMed=7687569

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