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Title: Elucidating the mechanisms of talin-mediated cellular mechanotransduction
Author: Haining, Alexander William Mackay
ISNI:       0000 0004 7969 8463
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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The ability of a cell to sense their physical environment, including tension and stiffness, has been implicated in a variety of cellular processes from development to disease. One of the key areas of research around this phenomenon concerns proteins whose three-dimensional structure is disrupted by physical forces in such a way as to alter how they behave. This class of 'mechanosensitive' molecules is thought to include a protein, talin, that is vital in the process of cellular attachment to the surrounding environment. Talin acts as a structural linkage in cells, bridging their internal scaffolding, the cytoskeleton, to the external environment. Here, using an advanced biophysical technique called single-molecule atomic force microscopy (smAFM), it is demonstrated that the majority of the talin molecule can be unfolded by pulling on either end. This unfolding occurs at forces that talin is likely to experience in cells, between 10 and 40 pN (these forces are 10^12 times smaller than the weight of gravity on 1kg). Using this smAFM technique, along with computer simulations provided by Vesa Hytönen's group at the University of Tampere, the pattern of how talin unfolds is demonstrated at an atomic level. This pattern is then shown to have similarities with other proteins that share a similar structure to talin. Thus the techniques and results shown here may serve as a template for the study of other structural proteins. Finally, protein engineering, smAFM and biophysical tools are used to show how the unfolding of talin may be linked to cancer progression. By mutating the talin protein, it was made resistant to unfolding and this increased its binding interaction with Deleted in Liver Cancer 1 (DLC1), a tumour suppressor protein that has been implicated in a variety of cancers. These results demonstrate the crucial role talin unfolding plays in cancer progression and offers a target for future therapeutic endeavours.
Supervisor: del Rio Hernandez, Armando Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral