Pathogenic bacteria attach to human fibronectin through a tandem β-zipper

Abstract

Staphylococcus aureus and Streptococcus pyogenes, two important human pathogens, target host fibronectin (Fn) in their adhesion to and invasion of host cells. Fibronectin-binding proteins (FnBPs), anchored in the bacterial cell wall, have multiple Fn-binding repeats in an unfolded region of the protein. The bacterium-binding site in the amino-terminal domain (1-5F1) of Fn contains five sequential Fn type 1 (F1) modules. Here we show the structure of a streptococcal (S. dysgalactiae) FnBP peptide (B3) in complex with the module pair 1F12F1. This identifies 1F1- and 2F1-binding motifs in B3 that form additional antiparallel beta-strands on sequential F1 modules-the first example of a tandem beta-zipper. Sequence analyses of larger regions of FnBPs from S. pyogenes and S. aureus reveal a repeating pattern of F1-binding motifs that match the pattern of F1 modules in 1-5F1 of Fn. In the process of Fn-mediated invasion of host cells, therefore, the bacterial proteins seem to exploit the modular structure of Fn by forming extended tandem beta-zippers. This work is a vital step forward in explaining the full mechanism of the integrin-dependent FnBP-mediated invasion of host cells.

Solution structure of a tethered Lmo2LIM2/Ldb1LID complex

“…It seems likely that the various disorder-to-order transitions associated with these different complexes cause the binding of the tandem LIM domains to be anti-cooperative (less than the sum of the free energies of the individual interactions). We and others have observed similar effects in the interactions of other modular binding interactions, including fibronectin-binding 31 and single-stranded RNA-binding systems. 32,33 In summary, comparison of the structures of several LIM-Ldb1 complexes indicates that the modular binding between Ldb1 and Lmo2 and related proteins is accompanied by a series of disorder-toorder transitions, particularly in Ldb1.…”

The N-terminal A Domain of Fibronectin-binding Proteins A and B Promotes Adhesion of Staphylococcus aureus to Elastin

“…Indeed, the FnBPA and FnBPB A domains bind to the C terminus of the ␥-chain of fibrinogen at the same site as ClfA and the platelet integrin (20,27). 10 fibronectin binding domains extend throughout domains B, C, and D of FnBPA (28,29), although most binding studies have been performed with the D repeats, such as D1D2D3 (30), which share 95% identity between both FnBPA and FnBPB. In this study, we have analyzed the molecular basis of adherence of S. aureus to immobilized elastin.…”

High Affinity Streptococcal Binding to Human Fibronectin Requires Specific Recognition of Sequential F1 Modules

“…1A) (8 -10). The FnBRs of SfbI are homologous to tandem repeats in FnBPs of other streptococci and Staphylococcus aureus, and new boundaries for FnBRs of both streptococci and staphylococci have recently been suggested based on structural data (7,11). FnBRs are intrinsically disordered and undergo a conformational change on binding to Fn (12)(13)(14).…”

“…The three-dimensional structure of an FnBP-derived peptide (B3 from S. dysgalactiae) in complex with 1 F1 2 F1 from the NTD of Fn was recently determined (11). The structure revealed an anti-parallel orientation of the binding partners with the peptide forming additional ␤-strands at the edge of the triple-stranded ␤-sheets of the two F1 modules.…”