{PDOC00022} {PS00023; FN2_1} {PS51092; FN2_2} {BEGIN} ********************************************************************* * 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 ) [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). -------------------------------------------------------------------------------- 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 https://prosite.expasy.org/prosite_license.html -------------------------------------------------------------------------------- {END}