Mechanotransduction by talin : a molecular dynamics study of force-induced recruitment of vinculin to a focal adhesion complex

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.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Mechanical Engineering.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2007

Author dc:creator

• Lee, Seung Eun, Ph. D. Massachusetts Institute of Technology

Advisor dc:contributor.advisor

• Roger D. Kamm and Mohammad R.K. Mofrad.

• Mechanical Engineering.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/42290

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/42290