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

André Krammer, David Craig, Wendy E. Thomas, Klaus Schulten, Viola Vogel

Research output: Contribution to journalArticlepeer-review


The synergy site on fibronectin's FN-III9 module, located approximately 32 Å away from the RGD-loop on FN-III10, greatly enhances integrin α5β1 mediated cell binding. Since fibronectin is exposed to mechanical forces acting on the extracellular matrix in vivo, we used steered molecular dynamics to study how mechanical stretching of FN-III9-10 affects the relative distance between these two synergistic sites. Our simulations predict the existence of an intermediate state prior to unfolding. In this state, the synergy-RGD distance is increased from 32 Å to approximately 55 Å, while the conformations of both sites remain unperturbed. This distance is too large for both sites to co-bind the same receptor, as indicated by experiments that confirm that increasing the length of the linker chain between FN-III9 and FN-III10 reduces α5β1 binding. Our simulations thus suggest that increased α5β1-binding attributed to the synergy site, along with the associated downstream cell-signaling events, can be turned off mechanically by stretching FN-III9-10 into this intermediate state. The potential physiological implications are discussed.

Original languageEnglish (US)
Pages (from-to)139-147
Number of pages9
JournalMatrix Biology
Issue number2
StatePublished - 2002


  • Fibronectin
  • Mechanical force
  • RGD loop
  • Steered molecular dynamics
  • Synergy site

ASJC Scopus subject areas

  • Molecular Biology

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