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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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Changes of intermodular distances and intermolecular hydrogen bonds formed between the FnI1–2–B3T complex as derived from steered molecular dynamic simulations.(a) Intermodular FnI1-FnI2 distance D (as defined in Fig. 5a) plotted versus time for three independently conducted SMD simulations (different colour traces). A constant force of 400 pN is applied at time zero to stretch Fn. The green curves correspond to the simulation, the structures of which are presented in Figure 5, at the time points indicated by the green arrows. (b) Total number of backbone hydrogen bonds formed between FnI1-2 and the peptide B3T versus time. (c) Total number of side-chain hydrogen bonds formed between FnI1–2 and the peptide B3T versus time.
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f6: Changes of intermodular distances and intermolecular hydrogen bonds formed between the FnI1–2–B3T complex as derived from steered molecular dynamic simulations.(a) Intermodular FnI1-FnI2 distance D (as defined in Fig. 5a) plotted versus time for three independently conducted SMD simulations (different colour traces). A constant force of 400 pN is applied at time zero to stretch Fn. The green curves correspond to the simulation, the structures of which are presented in Figure 5, at the time points indicated by the green arrows. (b) Total number of backbone hydrogen bonds formed between FnI1-2 and the peptide B3T versus time. (c) Total number of side-chain hydrogen bonds formed between FnI1–2 and the peptide B3T versus time.

Mentions: When stretching the FnI1-2 modules with an external mechanical force of 400 pN applied to its terminal ends, the β-sheet formed between FnI1 and B3T is destroyed after 2 ns of pulling (Fig. 5c,d and Supplementary Movie 1). In addition, we observe that the distance between FnI1 and FnI2 increases (green curve in Fig. 6a). This coincides with a decrease in the number of backbone hydrogen bonds formed between Fn and B3T (green curve in Fig. 6b). While stretching the FnI1-2 modules, the β-zipper motif formed with module FnI1 was disrupted, whereas the backbone hydrogen bonds formed between FnI2 and the bacterial peptide remained intact. In the second simulation, B3T detaches from FnI2 but remains bound to FnI1 (blue curves in Fig. 6a–c). In the third simulation, the number of backbone hydrogen bonds decreases only slightly (red curve in Fig. 6b). This is because the corresponding starting structure did not show a pronounced β-interaction between the carboxy (C)-terminus of B3T and FnI1 and thus fewer bonds were broken when compared with the other two trajectories. We also observe a small increase in side-chain hydrogen bonds formed between Fn1-2 and B3T (red curve in Fig. 6c), which are able to form near the C-terminus of B3T. However, similar to the observations in the other two simulations, the distance between FnI1 and FnI2 increases (red curve in Fig. 6a).


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

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

Changes of intermodular distances and intermolecular hydrogen bonds formed between the FnI1–2–B3T complex as derived from steered molecular dynamic simulations.(a) Intermodular FnI1-FnI2 distance D (as defined in Fig. 5a) plotted versus time for three independently conducted SMD simulations (different colour traces). A constant force of 400 pN is applied at time zero to stretch Fn. The green curves correspond to the simulation, the structures of which are presented in Figure 5, at the time points indicated by the green arrows. (b) Total number of backbone hydrogen bonds formed between FnI1-2 and the peptide B3T versus time. (c) Total number of side-chain hydrogen bonds formed between FnI1–2 and the peptide B3T versus time.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: Changes of intermodular distances and intermolecular hydrogen bonds formed between the FnI1–2–B3T complex as derived from steered molecular dynamic simulations.(a) Intermodular FnI1-FnI2 distance D (as defined in Fig. 5a) plotted versus time for three independently conducted SMD simulations (different colour traces). A constant force of 400 pN is applied at time zero to stretch Fn. The green curves correspond to the simulation, the structures of which are presented in Figure 5, at the time points indicated by the green arrows. (b) Total number of backbone hydrogen bonds formed between FnI1-2 and the peptide B3T versus time. (c) Total number of side-chain hydrogen bonds formed between FnI1–2 and the peptide B3T versus time.
Mentions: When stretching the FnI1-2 modules with an external mechanical force of 400 pN applied to its terminal ends, the β-sheet formed between FnI1 and B3T is destroyed after 2 ns of pulling (Fig. 5c,d and Supplementary Movie 1). In addition, we observe that the distance between FnI1 and FnI2 increases (green curve in Fig. 6a). This coincides with a decrease in the number of backbone hydrogen bonds formed between Fn and B3T (green curve in Fig. 6b). While stretching the FnI1-2 modules, the β-zipper motif formed with module FnI1 was disrupted, whereas the backbone hydrogen bonds formed between FnI2 and the bacterial peptide remained intact. In the second simulation, B3T detaches from FnI2 but remains bound to FnI1 (blue curves in Fig. 6a–c). In the third simulation, the number of backbone hydrogen bonds decreases only slightly (red curve in Fig. 6b). This is because the corresponding starting structure did not show a pronounced β-interaction between the carboxy (C)-terminus of B3T and FnI1 and thus fewer bonds were broken when compared with the other two trajectories. We also observe a small increase in side-chain hydrogen bonds formed between Fn1-2 and B3T (red curve in Fig. 6c), which are able to form near the C-terminus of B3T. However, similar to the observations in the other two simulations, the distance between FnI1 and FnI2 increases (red curve in Fig. 6a).

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