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{PDOC00022}
{PS00023; FN2_1}
{PS51092; FN2_2}
{BEGIN}
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* Fibronectin type-II collagen-binding domain signature and profile *
*********************************************************************

Fibronectin is a plasma protein that binds cell surfaces and various compounds
including  collagen,  fibrin,  heparin,  DNA, and actin. The major part of the
sequence  of fibronectin consists of the repetition of three types of domains,
which  are  called  type  I,  II,  and  III  [1].  Type  II  domain  (FN2)  is
approximately  40 residues long, contains four conserved cysteines involved in
disulfide bonds and is part of the collagen-binding region of fibronectin [2].
In  fibronectin  the  minimal collagen binding region is formed by one FN1 and
two  FN2 domains. This suggests that the collagen-binding sites spans multiple
modules.

A schematic representation of  the position  of the invariant residues and the
topology of the disulfide bonds in FN2 domain is shown below.

                        +----------------------+
                        |                      |
        xxCxxPFx#xxxxxxxCxxxxxxxxWCxxxxx#xxx#x#Cxx
          |                       |
          +-----------------------+

'C': conserved cysteine involved in a disulfide bond.
'#': large hydrophobic residue.

The  3D-structure of  the FN2 domain has been determined (see <PDB:2FN2>) [3].
The  structure  consists  of  two  double-stranded  anti-parallel beta-sheets,
oriented  approximately  perpendicular to each other, and two irregular loops,
one  separating  the  two beta-sheets and the other between the two strands of
the  second  beta-sheet.  The  minimal  collagen-binding  region (FN1-FN2-FN2)
adopts a hairpin structure where the conserved aromatic residues of FN2 form a
hydrophobic  pocket  which  is thought to provide a binding site for non polar
residues in collagen [4].

Some proteins that contain an FN2 domain are listed below:

 - Blood coagulation factor XII (Hageman factor) (1 copy).
 - Bovine seminal plasma proteins PDC-109 (BSP-A1/A2) and BSP-A3 [5] (twice).
 - Cation-independent mannose-6-phosphate receptor (which is also the insulin-
   like growth factor II receptor) [6] (1 copy).
 - Mannose receptor of macrophages [7] (1 copy).
 - 180 Kd secretory phospholipase A2 receptor (1 copy) [8].
 - DEC-205 receptor (1 copy) [9].
   72  Kd and 92 Kd type IV collagenases (EC 3.4.24.24) (MMP-2 and MMP-9) [10]
   (3  copies).  Both  metalloproteinases  are strongly expressed in malignant
   tumors  and  have  been  attributed  to  metastasize. They  both  degradate
   collagen-IV  thus  facilitating  penetration  of  the basement membranes by
   tumor cells.
 - Hepatocyte growth factor activator [11] (1 copy).

Our  consensus  pattern  spans  the  domain  between  the  first  and the last
conserved cysteine. We also developed a profile that covers the whole domain.

-Consensus pattern: C-x(2)-P-F-x-[FYWIV]-x(7)-C-x(8,10)-W-C-x(4)-[DNSR]-[FYW]-
                    x(3,5)-[FYW]-x-[FYWI]-C
                    [The 4 C's are involved in disulfide bonds]
-Sequences known to belong to this class detected by the profile: 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.

-Last update: March 2005 / Text revised; profile added.

[ 1] Skorstengaard K., Jensen M.S., Sahl P., Petersen T.E., Magnusson S.
     "Complete primary structure of bovine plasma fibronectin."
     Eur. J. Biochem. 161:441-453(1986).
     PubMed=3780752
[ 2] Forastieri H., Ingham K.C.
     "Interaction of gelatin with a fluorescein-labeled 42-kDa chymotryptic
     fragment of fibronectin."
     J. Biol. Chem. 260:10546-10550(1985).
     PubMed=3928622
[ 3] Pickford A.R., Potts J.R., Bright J.R., Phan I., Campbell I.D.
     "Solution structure of a type 2 module from fibronectin: implications
     for the structure and function of the gelatin-binding domain."
     Structure 5:359-370(1997).
     PubMed=9083105
[ 4] Pickford A.R., Smith S.P., Staunton D., Boyd J., Campbell I.D.
     "The hairpin structure of the (6)F1(1)F2(2)F2 fragment from human
     fibronectin enhances gelatin binding."
     EMBO J. 20:1519-1529(2001).
     PubMed=11285216; DOI=10.1093/emboj/20.7.1519
[ 5] Seidah N.G., Manjunath P., Rochemont J., Sairam M.R., Chretien M.
     "Complete amino acid sequence of BSP-A3 from bovine seminal plasma.
     Homology to PDC-109 and to the collagen-binding domain of
     fibronectin."
     Biochem. J. 243:195-203(1987).
     PubMed=3606570
[ 6] Kornfeld S.
     "Structure and function of the mannose 6-phosphate/insulinlike growth
     factor II receptors."
     Annu. Rev. Biochem. 61:307-330(1992).
     PubMed=1323236; DOI=10.1146/annurev.bi.61.070192.001515
[ 7] Taylor M.E., Conary J.T., Lennartz M.R., Stahl P.D., Drickamer K.
     "Primary structure of the mannose receptor contains multiple motifs
     resembling carbohydrate-recognition domains."
     J. Biol. Chem. 265:12156-12162(1990).
     PubMed=2373685
[ 8] Lambeau G., Ancian P., Barhanin J., Lazdunski M.
     "Cloning and expression of a membrane receptor for secretory
     phospholipases A2."
     J. Biol. Chem. 269:1575-1578(1994).
     PubMed=8294398
[ 9] Jiang W., Swiggard W.J., Heufler C., Peng M., Mirza A., Steinman R.M.,
     Nussenzweig M.C.
     "The receptor DEC-205 expressed by dendritic cells and thymic
     epithelial cells is involved in antigen processing."
     Nature 375:151-155(1995).
     PubMed=7753172; DOI=10.1038/375151a0
[10] Collier I.E., Wilhelm S.M., Eisen A.Z., Marmer B.L., Grant G.A.,
     Seltzer J.L., Kronberger A., He C., Bauer E.A., Goldberg G.I.
     J. Biol. Chem. 263:6579-6587(1988).
[11] Miyazawa K., Shimomura T., Kitamura A., Kondo J., Morimoto Y.,
     Kitamura N.
     J. Biol. Chem. 268:10024-10028(1993).

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