TCB Publications - Abstract

TCB Publications - Abstract

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$_{9}$, which is located about 32 Å away from the RGD-loop on FN-III$_{10}$, greatly enhances integrin ( $\alpha_{5}\beta_{1}$)-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$_{9-10}$ 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$_{9}$ and FN-III$_{10}$ reduces $\alpha_{5}\beta_{1}$ binding. Our simulations thus suggest that increased $\alpha_{5}\beta_{1}$-binding contributed by the synergy site, and associated downstream cell-signaling events, can be turned off mechanically by stretching FN-III$_{9-10}$ into this intermediate state. Under this model, $\alpha_{5}\beta_{1}$ 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$_{9-10}$ as the ?functionally decoupled? state and discuss its potential physiological implications.

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