Fibronectin type III repeat

The Ig-superfamily contains many proteins involved in immune recognition such as products of the MHC complex and accessory molecules [53]. In addition there are ten or more members associated mainly with nervous tissues in mature animals and several others in non-nervous tissue that are important factors in cell-cell and cell-substratum adhesion in non-immune cells. See [54] and [55] for detailed discussion of other aspects of Ig-superfamily glycoproteins. All of the cell adhesion glycoproteins in the family contain a variable number of Ig-like domains of about one hundred amino-acid residues, usually but not always defined within a pair of disulfide-bonded cysteine residues, and of the C2 type fold. In many cases the molecules contain variable numbers of another type of modular sequence known as the fibronectin type III repeat, sinee it was discovered in fibroneetin. In the following discussion, some principles of the structure and functions of this large family of cell adhesion molecules will be considered with particular emphasis on the interplay between different members in adhesion and modulation of adhesive interactions by carbohydrates. 

Fig. 8. Structures of LI, MAG and PO glycoproteins. The sequences of LI (a), MAG (b) and PO (c) glycoproteins predicted from analysis of cDNA clones as well as protein in the case of PO are shown to variably include in the extracellular portions Ig-like domains, fibronectin type III repeats (hatched), a transmembrane segment and a cytoplasmic domain. Potential A-glycosylation sites are indicated (open circle). Splicing variants in the cytoplasmic domains of LI and MAG are shown (open triangle).

Husmann, K., Faissner, A. and Schachner, M. (1992) Tenas-cin promotes cerebellar granule cell migration and neurite outgrowth by different domains in the fibronectin type III repeats. J. Cell Biol. 116 1475-1486. 

The cytoplasmic domains of all of these receptors have an intrinsic protein tyrosine kinase activity, and all the receptors have hydrophobic transmembrane sequences. Their extracellular regions are more variable in stmcture. Depending on the receptor, they may contain a range of domains, including (1) immrmoglobulin domains, (2) cysteine-rich motifs, (3) fibronectin type III repeats, and (4) EGF motifs. These can be present singly or in different combinations. Growth factor receptors are therefore examples of mosaic proteins. 

Another important family of chemorepellents was recently identified through genetic studies in Drosophila. In the roundabout (robo) mutant, axons fail to respect the midline boundary [47]. Robo protein was later identified as a transmembrane protein of the immunoglobulin superfamily with five immunoglobulin domains and three fibronectin type III repeats, and it was shown to be abundantly expressed on uncrossing axons [28], These findings led to the hypothesis that Robo functions as a receptor for a repellent of the midline. 

A FIGURE 6-25 Model of fibronectin binding to integrin through its RGD-containing type III repeat, (a) Scale model of fibronectin Is shown docked by two type III repeats to the extracellular domains of Integrin. Structures of fibronectin s domains were determined from fragments of the molecule. 

A synergy amino acid sequence, Pro-His-Ser-Aig-Asn (PHSRN), located in the 9th type III repeat of fibronectin (Figure 2), has been shown to improve bind-... 

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