Invited Paper NS1+BI-WeA2
Cell-Surface Interactions: The Extracellular Matrix as Mechanotransducer

Wednesday, October 17, 2007, 2:00 pm, Room 615

While cells initially respond to the surface chemistry presented on synthetic materials, they rapidly begin to assemble their own matrix. Cells can thereby sense and transduce a broad range of mechanical forces into distinct sets of biochemical signals that ultimately regulate cellular processes, including adhesion, proliferation, differentiation, and apoptosis. But how is force translated at the molecular level into biochemical signal changes that have the potential to alter cellular behavior? The molecular mechanism of fibronectin’s (Fn) extensibility within extracellular matrix fibrils is controversial. Does it originate from the force-induced extension of a compactly folded quaternary structure, or from unfolding of fibronectin modules? Clarification of this issue is central to our understanding whether or not the extracellular matrix can act as a mechanotransducer that converts mechanical forces into well regulated biochemical signal changes. Different fluorescence resonance energy transfer (FRET) labeling schemes were used to differentiate between these two models and we quantified how the conformational changes of fibronectin probed by FRET relate to changes of its overall end-to-end extension. The data clearly demonstrate that cells do indeed mechanically unfold fibronectin. The functional implications of the findings are discussed as well as high resolution structural models derived from steered molecular dynamics (SMD) how force might change the functional states of this and other multidomain proteins.