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


Project Description

The ability of cells to sense biochemical and mechanical properties of their extracellular matrix (ECM) environment is critical for the development of functional tissue. Aberrations in this process leads to severe health deficiencies including cancer, deficiencies in wound-healing and inflammation. The sensing of ECM is mediated by receptors (integrins) that bind with their extracellular domains to ECM proteins and with their intracellular domains to the contractile actomyosin cytoskeleton. The binding to the actin cytoskeleton is not direct but mediated and dynamically regulated through adapter proteins. Two of the key adapter proteins for ECM sensing are talin and vinculin. To co-ordinate ECM sensing and cell adhesion these two proteins undergo activation and de-activation processes involving conformational changes that lead to the unmasking of binding sites for other regulatory proteins. Understanding these conformational changes and its consequences for protein interactions may help us to provide new tools that can influence cell behaviour in a way that will allow to prevent diseases and supports regeneration.
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 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 conformation 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 Partnership. 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 website View Website

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

Atherton P, Lausecker F, Carisey A, Gilmore A, Critchley D, Barsukov I, Ballestrem C. Force-independent interactions of talin and vinculin govern integrin-mediated mechanotransduction. bioRxiv (2019) 629683; doi: https://doi.org/10.1101/629683 (under revision in Journal of Cell Biology)
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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