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Stretching fibronectin fibres disrupts binding of bacterial adhesins by physically destroying an epitope.

Chabria M, Hertig S, Smith ML, Vogel V - Nat Commun (2010)

Bottom Line: Heparin reduces binding but does not eliminate mechanosensitivity.The mechanical switch described here operates differently from the catch bond mechanism that Escherichia coli uses to adhere to surfaces under fluid flow.Demonstrating the existence of a mechanosensitive cell-binding site provides a new perspective on how the mechanobiology of ECM might regulate bacterial and cell-binding events, virulence and the course of infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Materials, ETH Zurich, Zürich CH-8093, Switzerland.

ABSTRACT
Although soluble inhibitors are frequently used to block cell binding to the extracellular matrix (ECM), mechanical stretching of a protein fibre alone can physically destroy a cell-binding site. Here, we show using binding assays and steered molecular dynamics that mechanical tension along fibronectin (Fn) fibres causes a structural mismatch between Fn-binding proteins from Streptococcus dysgalactiae and Staphylococcus aureus. Both adhesins target a multimodular site on Fn that is switched to low affinity by stretching the intermodular distances on Fn. Heparin reduces binding but does not eliminate mechanosensitivity. These adhesins might thus preferentially bind to sites at which ECM fibres are cleaved, such as wounds or inflamed tissues. The mechanical switch described here operates differently from the catch bond mechanism that Escherichia coli uses to adhere to surfaces under fluid flow. Demonstrating the existence of a mechanosensitive cell-binding site provides a new perspective on how the mechanobiology of ECM might regulate bacterial and cell-binding events, virulence and the course of infection.

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SMD simulation of the FnI1,2–B3T complex illustrating the molecular mechanism of strain-induced unbinding.(a) Equilibrated structure at 0 ns. Backbone hydrogen bonds between Fn modules (grey) and the bacterial peptide (green) are shown as orange springs and the intramodular FnI disulphide bond forming cysteine residues are represented in blue. The distance D is defined as the spacing between residues ASN55 on FnI1 and CYS104 on FnI2, which are located at the centre of the respective module's binding site for B3T. (b) Molecular surface representation of the same complex, colour-coded according to charge (neutral: white or green, positive: red, negative: blue). (c) The complex at 5 ns after having applied a constant force (black arrows) of 400 pN to the Fn termini. (d) Molecular surface representation at 5 ns, colour-coded according to charge (neutral: white or green, positive: red, negative: blue).
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f5: SMD simulation of the FnI1,2–B3T complex illustrating the molecular mechanism of strain-induced unbinding.(a) Equilibrated structure at 0 ns. Backbone hydrogen bonds between Fn modules (grey) and the bacterial peptide (green) are shown as orange springs and the intramodular FnI disulphide bond forming cysteine residues are represented in blue. The distance D is defined as the spacing between residues ASN55 on FnI1 and CYS104 on FnI2, which are located at the centre of the respective module's binding site for B3T. (b) Molecular surface representation of the same complex, colour-coded according to charge (neutral: white or green, positive: red, negative: blue). (c) The complex at 5 ns after having applied a constant force (black arrows) of 400 pN to the Fn termini. (d) Molecular surface representation at 5 ns, colour-coded according to charge (neutral: white or green, positive: red, negative: blue).

Mentions: To explore the underpinning mechanism by which tensile force exerting an effect on Fn fibres can disrupt bacterial-binding sites, we used SMD to simulate the stretching of FnI modules in complex with the bacterial peptide B3T (B3 truncated; Fig. 1c). The nuclear magnetic resonance structure of the FnI1-2–B3T complex15 (PDB 1O9A) was used as a starting structure for all simulations and hydrated in a box filled with explicit water molecules. The bacterial B3T peptide binds to both FnI modules by the antiparallel alignment of the two binding motifs on B3T with two distinct β-sheets formed by FnI1 and FnI2. For SMD simulations, the solvated system was equilibrated for 2 ns before applying constant tensile force (defined as t=0 ns; Fig. 5a,b). Three independent simulations were performed, each of which lasted for 7 ns.


Stretching fibronectin fibres disrupts binding of bacterial adhesins by physically destroying an epitope.

Chabria M, Hertig S, Smith ML, Vogel V - Nat Commun (2010)

SMD simulation of the FnI1,2–B3T complex illustrating the molecular mechanism of strain-induced unbinding.(a) Equilibrated structure at 0 ns. Backbone hydrogen bonds between Fn modules (grey) and the bacterial peptide (green) are shown as orange springs and the intramodular FnI disulphide bond forming cysteine residues are represented in blue. The distance D is defined as the spacing between residues ASN55 on FnI1 and CYS104 on FnI2, which are located at the centre of the respective module's binding site for B3T. (b) Molecular surface representation of the same complex, colour-coded according to charge (neutral: white or green, positive: red, negative: blue). (c) The complex at 5 ns after having applied a constant force (black arrows) of 400 pN to the Fn termini. (d) Molecular surface representation at 5 ns, colour-coded according to charge (neutral: white or green, positive: red, negative: blue).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3105298&req=5

f5: SMD simulation of the FnI1,2–B3T complex illustrating the molecular mechanism of strain-induced unbinding.(a) Equilibrated structure at 0 ns. Backbone hydrogen bonds between Fn modules (grey) and the bacterial peptide (green) are shown as orange springs and the intramodular FnI disulphide bond forming cysteine residues are represented in blue. The distance D is defined as the spacing between residues ASN55 on FnI1 and CYS104 on FnI2, which are located at the centre of the respective module's binding site for B3T. (b) Molecular surface representation of the same complex, colour-coded according to charge (neutral: white or green, positive: red, negative: blue). (c) The complex at 5 ns after having applied a constant force (black arrows) of 400 pN to the Fn termini. (d) Molecular surface representation at 5 ns, colour-coded according to charge (neutral: white or green, positive: red, negative: blue).
Mentions: To explore the underpinning mechanism by which tensile force exerting an effect on Fn fibres can disrupt bacterial-binding sites, we used SMD to simulate the stretching of FnI modules in complex with the bacterial peptide B3T (B3 truncated; Fig. 1c). The nuclear magnetic resonance structure of the FnI1-2–B3T complex15 (PDB 1O9A) was used as a starting structure for all simulations and hydrated in a box filled with explicit water molecules. The bacterial B3T peptide binds to both FnI modules by the antiparallel alignment of the two binding motifs on B3T with two distinct β-sheets formed by FnI1 and FnI2. For SMD simulations, the solvated system was equilibrated for 2 ns before applying constant tensile force (defined as t=0 ns; Fig. 5a,b). Three independent simulations were performed, each of which lasted for 7 ns.

Bottom Line: Heparin reduces binding but does not eliminate mechanosensitivity.The mechanical switch described here operates differently from the catch bond mechanism that Escherichia coli uses to adhere to surfaces under fluid flow.Demonstrating the existence of a mechanosensitive cell-binding site provides a new perspective on how the mechanobiology of ECM might regulate bacterial and cell-binding events, virulence and the course of infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Materials, ETH Zurich, Zürich CH-8093, Switzerland.

ABSTRACT
Although soluble inhibitors are frequently used to block cell binding to the extracellular matrix (ECM), mechanical stretching of a protein fibre alone can physically destroy a cell-binding site. Here, we show using binding assays and steered molecular dynamics that mechanical tension along fibronectin (Fn) fibres causes a structural mismatch between Fn-binding proteins from Streptococcus dysgalactiae and Staphylococcus aureus. Both adhesins target a multimodular site on Fn that is switched to low affinity by stretching the intermodular distances on Fn. Heparin reduces binding but does not eliminate mechanosensitivity. These adhesins might thus preferentially bind to sites at which ECM fibres are cleaved, such as wounds or inflamed tissues. The mechanical switch described here operates differently from the catch bond mechanism that Escherichia coli uses to adhere to surfaces under fluid flow. Demonstrating the existence of a mechanosensitive cell-binding site provides a new perspective on how the mechanobiology of ECM might regulate bacterial and cell-binding events, virulence and the course of infection.

Show MeSH
Related in: MedlinePlus