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(BBSRC DTP)Understanding structure and function of the mechanosensors talin and vinculin


Project Description

Any aberration in the cells’ ability to sense their environment leads to severe health deficiencies including cancer, deficiencies in wound-healing and inflammation. The cellular devices for sensing the extracellular properties are called focal adhesions (FA). At these sites, adhesion receptors (integrins) are linked to the contractile actomyosin cytoskeleton through focal adhesion plaque proteins. These proteins located at the interface between the adhesion receptors and the actin cytoskeleton, modulate and transmit biochemical and mechanical information from the cell’s outside environment to the inner milieu and vice versa. In recent studies we have identified the adhesion plaque proteins vinculin and talin as key adapter proteins regulating mechanosensing. How these two adapter proteins precisely interact is unclear and a detailed mechanistic insight will be required in order to understand their function in cells.

This project aims to gain information about structural rearrangements of talin and vinculin in inactive conformations and in active conformation when they associate with each other, the actin cytoskeleton and other proteins. This is often done by expressing recombinant proteins followed by in vitro association studies. However, such experiments depend on solubility of proteins and may not always represent the structural changes seen in cells. We therefore will develop a completely new assay that will allow us to assess (i) protein complex formation using super-resolution microscopy and FRET in cells and (ii) to isolate proteins in inactive and active conformations from cells to further assess their structure. The structure of such isolated proteins alone or in complex with other proteins will be assessed using Cryo EM and other supporting biochemical and biophysical approaches.

http://www.ballestremlab.com
http://www.wellcome-matrix.org/research_groups/clair-baldock.html

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the BBSRC Doctoral Training Programme. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the BBSRC DTP websitewww.manchester.ac.uk/bbsrcdtpstudentships

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Carisey, A. and Ballestrem, C. (2011). Vinculin, an adapter protein in control of cell adhesion signalling. Eur J Cell Biol. 90, 157-163;

Vinculin regulates the recruitment and release of core focal adhesion proteins in a force-dependent manner. Carisey A, Tsang R, Greiner AM, Nijenhuis N, Heath N, Nazgiewicz A, Kemkemer R, Derby B, Spatz J, Ballestrem C. Curr Biol. (2013) Feb 18;23(4):271-81.

Atherton, P., Stutchbury, B., Wang, D., Jethwa, D., Tsang, R., Meiler-Rodrigues, E., Wang, P., Bate, N., Zent, R., Barsukov, I.L., Goult, B.T., Critchley, D.R. and Ballestrem, C. (2015) Vinculin controls talin engagement with the actomyosin machinery. Nature Communications. 6:10038.

Ramsay EP, Collins RF, Owens TW, Siebert CA, Jones RPO, Wang T, Roseman AM, Baldock C. Structural analysis of X-linked retinoschisis mutations reveals distinct classes which differentially effect retinoschisin function. Hum Mol Genet. (2016) 25:5311-5320.

Godwin AR, Starborg T, Sherratt MJ, Roseman AM, Baldock C. Defining the hierarchical organisation of collagen VI microfibrils at nanometre to micrometre length scales. Acta Biomater. (2017) 52:21-32.

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