TCB Publications - Abstract

David Craig, André Krammer, Klaus Schulten, and Viola Vogel. Comparison of the early stages of forced unfolding of fibronectin type III modules. Proceedings of the National Academy of Sciences, USA, 98:5590-5595, 2001. (PMC: 33257)

CRAI2001 The structural changes accompanying stretch-induced early unfolding events were investigated for the four type III fibronectin (FN-III) modules, FN-III$_{7}$, FN-III$_{8}$, FN-III$_{9}$, and FN-III$_{10}$ by using steered molecular dynamics. Simulations revealed that two main energy barriers, I and II, have to be overcome to innitiate unraveling of FN-III's tertiary structure. In crossing the first barrier, the two opposing $\beta$-sheets of FN-III are rotated against each oher such that the $\beta$-strands of both $\beta$-sheets align parallel to the force vector (aligned state). All further events in the unfolding pathway proceed from this inermediate state. A second energy barrier has to be overcome to break the first major cluster of hydrogen bonds between adjacent $\beta$-strands. Simulations revealed that the height of barrier I varied significantly among the four modules studied, being largest for FN-III$_{7}$ and lowest for FN-III$_{10}$, whereas the height of barrier II showed little variation. Key residues affecting the mechanical stability of FN-III modules were identified. these results suggest that FN-III modules can be prestretched into an intermediate state with only minor changes to their tertiary structures. FN-III$_{10}$, for example, extends 12Åfrom the native "twisted" to the intermediate aligned state, and an additional 10Åfrom the aligned state to further unfolding where the first $\beta$-strand is peeled away. The implications of the existence of intermediate states regarding the elasticity of fibrillar fibers and the stretch-induced exposure of cryptic sites are discussed.

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