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Regulation of synaptic protein function by protein palmitoylation

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Palmitoylation (S-acylation), the only known reversible lipid modification of proteins, is an important regulator of protein localisation and function. It affects a plethora of cellular processes including protein trafficking, stability and signalling and is therefore important for all cell types, and organisms from yeast to humans. The extent to which this reversible post-translational modification is employed and how the specificity of the palmitoylation machinery is encoded remains to be determined.

Palmitoylation is mediated by a family of 23 enzymes (protein acyl transferases (PATs)) in humans. Many of these enzymes have been shown to regulate important aspects of cell biology and in particular in neuronal cells where palmitoylation of receptors and associated proteins regulates synaptic plasticity and therefore functions such as learning and memory. Indeed, several of these enzymes have been implicated in the pathophysiology of neurological disorders from Huntington’s disease to intellectual disability and schizophrenia.

It is not well understood which proteins are modified by individual PATs in cells, how they can selectively recognise substrate proteins and what effect palmitoylation has on the function of these proteins. This project will use proteomic approaches that we have recently developed to identify substrates of protein acyl transferases and investigate how palmitoylation of selected substrates regulates their stability, trafficking and function. This interdisciplinary project will utilise a range of experimental approaches including cell culture, molecular and cell biology, biochemistry and state-of-the-art quantitative mass spectrometry. The student will be given in-depth training in all of these methods and will benefit from collaborations with other groups within the department.

This research will further our understanding of how proteins dynamically associate with membranes and how this affects their function in health and disease.

Science Graduate School
As a PhD student in one of the science departments at the University of Sheffield, you’ll be part of the Science Graduate School. You’ll get access to training opportunities designed to support your career development by helping you gain professional skills that are essential in all areas of science. You’ll be able to learn how to recognise good research and research behaviour, improve your communication abilities and experience the breadth of technologies that are used in academia, industry and many related careers. Visit http://www.sheffield.ac.uk/sgs to learn more.

Funding Notes

First class or upper second 2(i) in a relevant subject. To formally apply for a PhD, you must complete the University's application form using the following link: View Website
All applicants should ensure that both references are uploaded onto their application as a decision will be unable to be made without this information.

References

Woodley KT, Collins MO. S-acylated Golga7b stabilises DHHC5 at the plasma membrane to regulate cell adhesion. EMBO Rep. 2019 Aug 12:e47472.

Collins MO, Woodley KT, Choudhary JS. Global, site-specific analysis of neuronal protein S-acylation. Sci Rep. 2017 Jul 5;7(1):4683.

Fernández E, Collins MO, Frank RAW, Zhu F, Kopanitsa MV, Nithianantharajah J, Lemprière SA, Fricker D, Elsegood KA, McLaughlin CL, Croning MDR, Mclean C, Armstrong JD, Hill WD, Deary IJ, Cencelli G, Bagni C, Fromer M, Purcell SM, Pocklington AJ, Choudhary JS, Komiyama NH, Grant SGN. Arc Requires PSD95 for Assembly into Postsynaptic Complexes Involved with Neural Dysfunction and Intelligence. Cell Rep. 2017 Oct 17;21(3):679-691.

Bayés A, van de Lagemaat LN, Collins MO, Croning MD, Whittle IR, Choudhary JS, Grant SG. (2011). Characterization of the proteome, diseases and evolution of the human postsynaptic density. Nature Neuroscience. Jan;14(1):19-21.

http://www.sheffield.ac.uk/bms/research/collins/index

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