Mechanotransduction by talin : a molecular dynamics study of force-induced recruitment of vinculin to a focal adhesion complex
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232158757-MIT.pdf
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Author(s)
Lee, Seung Eun, Ph. D. Massachusetts Institute of Technology
Advisor(s)
Roger D. Kamm and Mohammad R.K. Mofrad.
Alternative Title
Molecular dynamics study of force-induced recruitment of vinculin to a focal adhesion complex
Date Issued
2007
Publisher
Massachusetts Institute of Technology
Abstract
It is now well established that cells can sense mechanical force, but the mechanisms by which force is transduced into a biochemical signal remain poorly understood. One example is the recruitment of vinculin to reinforce initial contacts between a cell and the extracellular matrix due to tensile force. Talin, an essential structural protein in the adhesion, contains the N-terminal five-helix bundle in the rod domain with a known cryptic vinculin binding site 1 (VBS1). The perturbation of this stable structure through elevated temperature or destabilizing mutation activates vinculin binding. Here, molecular dynamics (MD) is employed to demonstrate a force-induced conformational change that exposes the cryptic vinculin-binding-residues of VBS1 to solvent under applied forces along a realistic pulling direction. VBS 1 undergoes a rigid body rotation by an applied torque transmitted through hydrogen-bonds and salt bridges. Activation was observed with mean force of 13.2±8.0pN during constant velocity simulation and with steady force greater than 18.0pN. The crystal structure of vinculin head subdomain (Vhl) bound to the talin VBS1 implies that vinculin undergoes a large conformational change upon binding to talin, but the molecular basis for this, or the precise nature of the binding pathway remain elusive. In the second part of the thesis, MD is employed to investigate the binding mechanism of Vhl and VBS1 with minimal constraints to facilitate the binding. One simulation demonstrates binding of the two molecules in the complete absence of external force. VBS1 makes early hydrophobic contact with Vhl through an initial hydrophobic insertion. Then, other solvent-exposed hydrophobic residues of VBS1 gradually embed into the hydrophobic core of Vhl further displacing helix 1 from helix 2.
(cont.) These highly conserved critical residues are experimentally shown to be essential in Vhl-VBS1 binding, and are also the same residues that are shown to become exposed by applied tension to talin in the first part of the thesis. Similar mechanisms are demonstrated in separate MD simulations of Vhl binding to other VBSs both in talin and a-actinin. Together, these results provide molecular insights, for the first time, into the early force-induced recruitment of vinculin to the mechanosensitive mechanisms of cell-matrix adhesion complex, and establish the basis for further numerical and experimental studies to fully understand the force response of focal adhesions.
Description
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2007.
Includes bibliographical references (p. 112-123).
Subjects
Mechanical Engineering.
MIT Department
Massachusetts Institute of Technology. Department of Mechanical Engineering
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