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Click here to search FindAPhD.com for PhD studentship opportunitiesAbout the Project
Proteins carry out key functions in cells, and frequently perform these roles in the context of multi-subunit complexes. Traditionally, individual proteins were thought to be synthesised separately and then find each other to assemble into complexes post-translationally through the highly complex and crowded molecular environment within the cell. However, it is clear for cytosolic proteins that this process occurs at a co-translational level while one of more of the components is still being synthesised. Colocalisation of assembly is assisted by the colocalisation of the respective mRNAs. This system brings many advantages since it allows production of proteins in close proximity so they can readily assemble. It can also link to ‘translational factories’ where the translation machinery can be concentrated, and importantly, it can prevent aggregation of proteins that are unstable outside of their complex, which can lead to disease.
Secretory and membrane proteins also similarly form multi-subunit complexes, but their co-translational assembly has been less well studied to date. In part this stems from increased complexity since it involves translocation across/ or insertion into the ER membrane. Antibodies, which are composed of two light and two heavy chains represent excellent examples. There is accumulating evidence that, as with cytosolic proteins, this process can also occur co-translationally.
This project will develop tools to visualise in living cells the location of specific secretory and membrane protein mRNAs as well as where active translation of these mRNAs is occurring. By specifically looking at the localisation of mRNA and translation of proteins within the same complex this will allow the extent of co-translational assembly to be determined. The project will initially use yeast as a genetically-tractable model system where the above approach is already established for cytosolic proteins. The localisation of mRNA and translation of model complexes, and in particular ion transporters, will be tested using this approach.
Once established in yeast the project will also transfer this approach to mammalian cells so this process can be assessed for disease-relevant protein complexes including collagen, potassium-gated ion channels and ERp57/calreticulin. Overall, the project will provide new understanding into the prevalence and importance of co-translational assembly of secretory and membrane proteins. Insight into this fundamentally important process will be highly relevant to understanding healthy ageing and also has direct relevance for the enhanced production of antibodies and other therapeutics in both yeast and mammalian systems.
Eligibility
Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science, engineering or technology.
Before you Apply
Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.
How To Apply
To be considered for this project you MUST submit a formal online application form - full details on eligibility how to apply can be found on the BBSRC DTP website https://www.bmh.manchester.ac.uk/study/research/funded-programmes/bbsrc-dtp/
Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application please contact our admissions team [Email Address Removed]
Equality, Diversity and Inclusion
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 https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/
Funding Notes
References
Shiber et al. Nature. 2018 561:268-272 3.
Pizzinga et al. J Cell Biol. 2019 218:1564-1581.
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