Limits...
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.

Show MeSH

Related in: MedlinePlus

Intermolecular backbone hydrogen and side chain hydrogen bond fluctuations within the FnI1–2–B3T complex plotted over simulation time.Residues on FnI1–2 are listed in black text and residues on B3T in green. Only bonds that were present during 0.3 ns or longer are shown. Constant external force of 400 pN was applied starting at 0 ns. Backbone hydrogen bonds (orange) between FnI1 and B3T are disrupted at ∼1 ns (PHE54-PHE28 and CYS56-ILE26), whereas FnI2 stays bound to B3T (ILE102-GLU18 and CYS104-GLU16). The total numbers of intermolecular hydrogen bonds for this simulation are plotted in the green curve in Figure 6, and the corresponding structures are displayed in Figure 5. Side chain hydrogen bonds are displayed in black.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3105298&req=5

f7: Intermolecular backbone hydrogen and side chain hydrogen bond fluctuations within the FnI1–2–B3T complex plotted over simulation time.Residues on FnI1–2 are listed in black text and residues on B3T in green. Only bonds that were present during 0.3 ns or longer are shown. Constant external force of 400 pN was applied starting at 0 ns. Backbone hydrogen bonds (orange) between FnI1 and B3T are disrupted at ∼1 ns (PHE54-PHE28 and CYS56-ILE26), whereas FnI2 stays bound to B3T (ILE102-GLU18 and CYS104-GLU16). The total numbers of intermolecular hydrogen bonds for this simulation are plotted in the green curve in Figure 6, and the corresponding structures are displayed in Figure 5. Side chain hydrogen bonds are displayed in black.

Mentions: In all three simulations, stretching Fn causes a structural mismatch leading to partial detachment of B3T from FnI1-2, where the formation of the tandem β-zipper is partially destroyed and reduced to a monomodular interaction between the bacterial peptide and one of the FnI modules. The number of side-chain hydrogen bonds fluctuates significantly and differs among simulations because of the large mobility of the bacterial peptide once it partially disconnects from the Fn fragment (Fig. 6c). However, in all our previous simulations of β-sheet motifs, we found that the major force-bearing interactions were defined by backbone and not by side-chain interactions3536. A detailed overview of both backbone and side-chain intermolecular hydrogen bonds observed in the first simulation can be found in Figure 7. Our conclusions derived from this computational analysis agree with a very recent and independently conducted simulation37. Taken together, the insights gained from SMD simulations provide a high-resolution structural mechanism that shows how mechanical force pulling on Fn can affect the interaction between B3 and FnI1-2, thereby offering an explanation for the experimentally observed decrease in binding of the bacterial peptide to stretched Fn fibres.


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

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

Intermolecular backbone hydrogen and side chain hydrogen bond fluctuations within the FnI1–2–B3T complex plotted over simulation time.Residues on FnI1–2 are listed in black text and residues on B3T in green. Only bonds that were present during 0.3 ns or longer are shown. Constant external force of 400 pN was applied starting at 0 ns. Backbone hydrogen bonds (orange) between FnI1 and B3T are disrupted at ∼1 ns (PHE54-PHE28 and CYS56-ILE26), whereas FnI2 stays bound to B3T (ILE102-GLU18 and CYS104-GLU16). The total numbers of intermolecular hydrogen bonds for this simulation are plotted in the green curve in Figure 6, and the corresponding structures are displayed in Figure 5. Side chain hydrogen bonds are displayed in black.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f7: Intermolecular backbone hydrogen and side chain hydrogen bond fluctuations within the FnI1–2–B3T complex plotted over simulation time.Residues on FnI1–2 are listed in black text and residues on B3T in green. Only bonds that were present during 0.3 ns or longer are shown. Constant external force of 400 pN was applied starting at 0 ns. Backbone hydrogen bonds (orange) between FnI1 and B3T are disrupted at ∼1 ns (PHE54-PHE28 and CYS56-ILE26), whereas FnI2 stays bound to B3T (ILE102-GLU18 and CYS104-GLU16). The total numbers of intermolecular hydrogen bonds for this simulation are plotted in the green curve in Figure 6, and the corresponding structures are displayed in Figure 5. Side chain hydrogen bonds are displayed in black.
Mentions: In all three simulations, stretching Fn causes a structural mismatch leading to partial detachment of B3T from FnI1-2, where the formation of the tandem β-zipper is partially destroyed and reduced to a monomodular interaction between the bacterial peptide and one of the FnI modules. The number of side-chain hydrogen bonds fluctuates significantly and differs among simulations because of the large mobility of the bacterial peptide once it partially disconnects from the Fn fragment (Fig. 6c). However, in all our previous simulations of β-sheet motifs, we found that the major force-bearing interactions were defined by backbone and not by side-chain interactions3536. A detailed overview of both backbone and side-chain intermolecular hydrogen bonds observed in the first simulation can be found in Figure 7. Our conclusions derived from this computational analysis agree with a very recent and independently conducted simulation37. Taken together, the insights gained from SMD simulations provide a high-resolution structural mechanism that shows how mechanical force pulling on Fn can affect the interaction between B3 and FnI1-2, thereby offering an explanation for the experimentally observed decrease in binding of the bacterial peptide to stretched Fn fibres.

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