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How mutations in myosin lead to diseases such as deafness.

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  • Full or part time
    Prof M Peckham
    Prof N A Ranson
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Non-muscle myosin 2A (NM2A) is implicated in a range of diseases from cancer, to defective blood clotting and deafness (1). Common to all of these diseases is the likelihood that the regulation of NM2A is disrupted, however we only have a poor understanding of the structure and regulation of NM2A. The main goal of this project is to understand how non-muscle myosin 2A switches between its ’off’ (folded) state and its ’on’ active state, which forms filaments, and how mutations affect this behaviour. To achieve this, you will learn to use a combination of approaches, from molecular cloning (to introduce mutations, and generate expression constructs), cell biology (to express normal and mutant proteins in cells and perform high resolution light microscopy (including super-resolution microscopy (2,3,4)) to investigate how it behaves in live and fixed cells), in vitro motility assays (to investigate the properties of the myosin in vitro), circular dichroism (to investigate effects of mutations on secondary structure (5)), protein expression in E. coli and Sf9 cells (to express protein domains and full length protein for in vitro assays), and electron microscopy (negative stain and cryo-EM) to assess effects of mutations on structure.

Funding Notes

BBSRC White Rose Mechanistic Biology DTP 4 year studentship.
Studentships covers UK/EU fees and stipend (c.£14,296) for 4 years to start in Oct 2017. Applicants should have/be expecting at least a 2.1 Hons. degree in a relevant subject. EU candidates require 3 years of UK residency in order to receive full studentship.
Not all projects advertised will be funded; the DTP will appoint a limited number of candidates via a competitive process and the projects selected by the successful candidates will be funded.
There are 2 stages to the application process. Please see our website for more information: http://www.fbs.leeds.ac.uk/postgraduate/phdopportunities.php

References

1. Peckham, M. (2016) How myosin organisation of the cytoskeleton contributes to the cancer phenotype. (2016) Biochem. Soc. Trans. 44, 1026-34
2. Baboolal T.G., Mashanov, G.I., Nenasheva, T.A., Peckham, M*. and Molloy, J.E. (2016) A combination of diffusion and active translocation localizes Myosin 10 to the filopodial tip. J. Biol. Chem. 291, 22373-22385
3. Lambacher, M.J., Bruel, A-L. van Dam, T. J. P, Szymańska, K., Slaats. G.G., Stefanie Kuhns, S., McManus, G.J., Kennedy, J.E., Gaff, K., Wu, K.M., Van der Lee, R., Burglen, L., Doummar, D., Rivière,J.B., Faivre, L., Attié-Bitach, T., Saunier, S., Curd, A., Peckham, M., Giles, R., Johnson, C.A., Huynen, M.A., Thauvin-Robinet, C., Blacque, O.E. (2016) TMEM107 recruits ciliopathy proteins to anchored periodic subdomains of the ciliary transition zone membrane and is mutated in Joubert syndrome. Nature Cell Biology 18: 122-31
4. Makowska, K.A., Hughes, R.E., White, K.J., Wells, C.M., Peckham, M. (2015) Specific myosins control actin organization, cell morphology and migration in prostate cancer cells. Cell Reports 13:2118-25
5. Wolny, M., Colegrave, M., Colman, L., White, E., Knight, P. J., and Peckham, M. (2013) Cardiomyopathy mutations in the tail of beta-cardiac myosin modify the coiled-coil structure and affect integration into thick filaments in muscle sarcomeres in adult cardiomyocytes. J Biol Chem 288, 31952-31962


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