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About the Project
Over the past 15 years, much has been learned about how protein folding in the cytoplasm and the lumen of the endoplasmic reticulum is monitored (Christianson and Ye, 2014). However, little is currently known about how defective membrane spanning domains are recognised. We have recently found that quality control checkpoints at the endoplasmic reticulum (Briant et al., 2015), Golgi apparatus and plasma membrane are able to recognise a simple model protein containing a defective transmembrane domain.
The aim of this project is to further define these quality control pathways using the peripheral myelin membrane protein PMP22. Missense mutations in PMP22 cause peripheral neuropathies including Charcot-Marie-Tooth (CMT) disease, and several of the disease-causing mutations are known to disrupt the proper arrangement of transmembrane domains (Schlebach et al., 2015), making PMP22 an attractive model for these studies. The results of this work will lead to greater understanding of the molecular mechanisms that maintain the quality of the membrane proteome, and also provide new insight into the molecular basis of PMP22 related diseases.
A range of cell biology, biochemistry, molecular biology, bioimaging and proteomic methods will be utilised, including mammalian cell culture, generation of stable cell lines, expression of disease-associated mutant proteins, siRNA knockdown, immunofluorescence microscopy, SDS-PAGE and western blotting, immunoprecipitation, mass spectrometry, molecular cloning and site directed mutagenesis.
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area such as Biochemistry, Cell Biology, Biomedical Sciences, Neurosciences.
Funding Notes
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website View Website
References
Christianson, J. C. and Ye, Y. (2014). Cleaning up in the endoplasmic reticulum: ubiquitin in charge. Nat Struct Mol Biol 21, 325-35
Ng, D. P., Poulsen, B. E. and Deber, C. M. (2012). Membrane protein misassembly in disease. Biochim Biophys Acta 1818, 1115-22.
Schlebach, J. P., Narayan, M., Alford, C., Mittendorf, K. F., Carter, B. D., Li, J. and Sanders, C. R. (2015). Conformational Stability and Pathogenic Misfolding of the Integral Membrane Protein PMP22. J Am Chem Soc 137, 8758-68.
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