PROSITE documentation PDOC00022

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 β-sheets, oriented approximately perpendicular to each other, and two irregular loops, one separating the two β-sheets and the other between the two strands of the second β-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.