Mu Gao, David Craig, Olivier Lequin, Iain D. Campbell, Viola Vogel, and Klaus
Schulten.
Structure and functional significance of mechanically unfolded
fibronectin type III1 intermediates.
Proceedings of the National Academy of Sciences, USA,
100:14784-14789, 2003.
(PMC: 299803)
GAO2003
Fibronectin (FN) forms fibrillar networks coupling cells to the
extracellular matrix (ECM). The formation of FN fibrils, fibrillogenesis,
is a tightly regulated process involving the exposure of cryptic binding
sites in individual FN type III (FN-III) repeats presumably exposed by
mechanical tension. The FN-III1 module has been previously proposed to
contain such cryptic sites that promote the assembly of extracellular
matrix FN fibrils. We have combined NMR and steered molecular dynamics
(SMD) simulations to study the structure and mechanical unfolding pathway
of FN-III1. This study finds that FN-III1 consists of a beta-sandwich
structure that unfolds to a mechanically stable intermediate which is
about four times the length of the native folded state. Considering
previous experimental findings, our studies provide a structural model by
which mechanical stretching of FN-III1 may induce fibrillogenesis through
this partially unfolded intermediate.
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