A structural model for force regulated integrin binding to fibronectin's RGD-synergy site

Area of Science:

• Biochemistry
• Molecular Biology
• Biophysics

Background:

• Fibronectin's FN-III(9) synergy site and FN-III(10) RGD-loop are crucial for integrin alpha(5)beta(1) binding.
• Extracellular matrix proteins like fibronectin experience mechanical forces in vivo.

Purpose of the Study:

• To investigate the effect of mechanical stretching on the distance between fibronectin's synergy and RGD sites.
• To understand how mechanical forces modulate integrin alpha(5)beta(1) binding to fibronectin.

Main Methods:

• Steered molecular dynamics simulations were employed to model mechanical stretching of the FN-III(9-10) module.
• Analysis focused on the conformational changes and relative distances between the synergy and RGD sites.

Main Results:

• Simulations revealed an intermediate state upon stretching, increasing the synergy-RGD distance from 32 Å to approximately 55 Å.
• This increased distance prevents co-binding of both sites to the same integrin receptor, consistent with experimental data.
• The conformations of the synergy and RGD sites remained unperturbed in this intermediate state.

Conclusions:

• Mechanical stretching of fibronectin's FN-III(9-10) module can mechanically regulate integrin alpha(5)beta(1) binding.
• This mechanical regulation occurs by increasing the distance between the synergy and RGD sites, effectively "turning off" binding.
• Findings suggest a mechanism for controlling cell signaling through mechanical forces on the extracellular matrix.