André Krammer, David Craig, Wendy E. Thomas, Klaus Schulten, and Viola
Vogel.
A structural model for force regulated integrin binding to
fibronectin's RGD-synergy site.
Matrix Biology, 21:139-147, 2002.
KRAM2002
The presence of the synergy site on fibronectin?s module FN-III, which is located about 32 Å away from the RGD-loop on FN-III, greatly enhances integrin (
)-mediated cell binding. Since fibronectin is exposed to mechanical forces acting on the extracellular matrix in vivo, we use steered molecular dynamics (SMD) to study how mechanical stretching of
FN-III affects the relative distance between the two synergistic sites. Prior to force-induced unfolding of the
modules, our simulations find the existence of an intermediate state in which the synergy-RGD distance is increased to approximately 55 Å while both the conformations of the RGD-loop and the synergy site themselves are unperturbed. This synergy-RGD distance is too large for the RGD-loop and the synergy site to co-bind the same receptor molecule; they are thus functionally decoupled. It has also been experimentally found that an increase in the linker chain length between FN-III and FN-III reduces
binding. Our simulations thus suggest that increased
-binding contributed by the synergy site, and associated downstream cell-signaling events, can be turned off mechanically by stretching FN-III into this intermediate state. Under this model,
binding to the RGD-synergy site can be reduced under tension without deforming the separate binding sites and thus not affecting binding of integrins to the RGD-loop alone. We thus define this structural intermediate state of FN-III as the ?functionally decoupled? state and discuss its potential physiological implications.
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