FC0020
Fibronectin binding protein (FnBP) SfbI  -  Fibronectin, Fn3

Biological function
Fibronectin (Fn) binding by the Streptococcus pyogenes protein SfbI has been shown to trigger integrin-dependent internalization of this pathogen by human epithelial and endothelial cells. The FnBP SfbI has been shown to efficiently mediate cellular internalization; in the uptake process Fn acts as a bridge between the pathogens and integrin receptors on the cell surface.

Structural evidence
Based on NMR and ITC data, each of the five Fn type 1 modules is directly involved in the interaction and is recognized by short consecutive motifs within the repeat region of SfbI.

Biochemical evidence
Various Fn binding peptides indicate SfbI motifs must be combined in the correct order to form a high affinity ligand for the N- terminal domain of Fn. The ³F1 and ⁵F1 binding motifs do not show a binding activity on their own, but enhance binding affinity when linked to ²F1 and ⁴F1 motifs. The ³F1-binding segment also contributes significantly to the affinity of the two-module binding peptide. The ²F1³F1-binding binding motif is located outside the Fn binding repeats. The unstructured UR region also contributes to high-affinity binding to Fn. The K_D is not equal to the product of affinities of the subdomains, owing to the unstructured linkers and the dependence on the ionic strength.

Structure/Mechanism
The structure revealed an anti-parallel orientation of the binding partners with the peptide forming additional β-strands at the edge of the triple-stranded β -sheets of the two F1 modules. This novel binding mechanism was named a ’tandem β -zipper’. Each of the five F1 modules of the NTD is specifically recognized by short, consecutive amino acid sequences in FnBRs. A functional FnBR is a linear array of these F1-binding motifs, arranged in the correct order to bind 1:1 to the NTD in an anti- parallel fashion. The common structural theme of F1 recognition is the β-zipper. The bacterial motifs binding the individual modules primarily by forming an additional β -strand along the E-strand of each F1 module. As a result, bound FnBRs form a large intermolecular surface with their modular target.

Mechanism category
tethering

Significance
The fuzzy linkers between the consensus FnBP motifs enable combinatorial usage of the binding sites to increase binding affinity and ensure selectivity control.

Further reading
12736686