TCB Publications - Abstract

David Craig, Mu Gao, Klaus Schulten, and Viola Vogel. Tuning the mechanical stability of fibronectin type III modules through sequence variation. Structure, 12:21-30, 2004.

CRAI2004 Cells can switch the functional states of proteins by exerting mechanical forces that stretch them out of their equilibrium state. Using steered molecular dynamics, we investigated how variations in the amino acid sequence of FnIII modules from the cell adhesion protein fibronectin affect their mechanical stability. Despite remarkably similar tertiary structures, FnIII modules share low sequence homology. Conversely, the sequence homology for the same FnIII module across multiple species is notably higher suggesting that sequence variability is functionally significant. Our studies find that the mechanical stability of FnIII modules can be tuned by substitutions of just a few key amino acids by altering access of hydrogen bond that break early in the unfolding pathway to attack by water molecules. Furthermore, the FnIII hierarchy of mechanical unfolding can be changed by environmental conditions, such as pH for FnIII$_{10}$, or by forming complexes with other molecules, such as heparin binding to FnIII$_{13}$.

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