Mechanotransduction by talin : a molecular dynamics study of force-induced recruitment of vinculin to a focal adhesion complex
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2007.
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| Format: | Thesis |
| Language: | eng |
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Massachusetts Institute of Technology
2008
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| Online Access: | http://hdl.handle.net/1721.1/42290 |
| _version_ | 1811093422928297984 |
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| author | Lee, Seung Eun, Ph. D. Massachusetts Institute of Technology |
| author2 | Roger D. Kamm and Mohammad R.K. Mofrad. |
| author_facet | Roger D. Kamm and Mohammad R.K. Mofrad. Lee, Seung Eun, Ph. D. Massachusetts Institute of Technology |
| author_sort | Lee, Seung Eun, Ph. D. Massachusetts Institute of Technology |
| collection | MIT |
| description | Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2007. |
| first_indexed | 2024-09-23T15:44:49Z |
| format | Thesis |
| id | mit-1721.1/42290 |
| institution | Massachusetts Institute of Technology |
| language | eng |
| last_indexed | 2024-09-23T15:44:49Z |
| publishDate | 2008 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/422902019-04-12T13:52:26Z Mechanotransduction by talin : a molecular dynamics study of force-induced recruitment of vinculin to a focal adhesion complex Molecular dynamics study of force-induced recruitment of vinculin to a focal adhesion complex Lee, Seung Eun, Ph. D. Massachusetts Institute of Technology Roger D. Kamm and Mohammad R.K. Mofrad. Massachusetts Institute of Technology. Dept. of Mechanical Engineering. Massachusetts Institute of Technology. Dept. of Mechanical Engineering. Mechanical Engineering. Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2007. Includes bibliographical references (p. 112-123). 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. by Seung Eun Lee. Ph.D. 2008-09-03T15:14:07Z 2008-09-03T15:14:07Z 2007 2007 Thesis http://hdl.handle.net/1721.1/42290 232158757 eng 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. http://dspace.mit.edu/handle/1721.1/7582 149 p. application/pdf Massachusetts Institute of Technology |
| spellingShingle | Mechanical Engineering. Lee, Seung Eun, Ph. D. Massachusetts Institute of Technology Mechanotransduction by talin : a molecular dynamics study of force-induced recruitment of vinculin to a focal adhesion complex |
| title | Mechanotransduction by talin : a molecular dynamics study of force-induced recruitment of vinculin to a focal adhesion complex |
| title_full | Mechanotransduction by talin : a molecular dynamics study of force-induced recruitment of vinculin to a focal adhesion complex |
| title_fullStr | Mechanotransduction by talin : a molecular dynamics study of force-induced recruitment of vinculin to a focal adhesion complex |
| title_full_unstemmed | Mechanotransduction by talin : a molecular dynamics study of force-induced recruitment of vinculin to a focal adhesion complex |
| title_short | Mechanotransduction by talin : a molecular dynamics study of force-induced recruitment of vinculin to a focal adhesion complex |
| title_sort | mechanotransduction by talin a molecular dynamics study of force induced recruitment of vinculin to a focal adhesion complex |
| topic | Mechanical Engineering. |
| url | http://hdl.handle.net/1721.1/42290 |
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