Post-translational modifications mediated by carbon dioxide
Carbon dioxide is vital to life processes that include metabolism, cellular homeostasis, chemosensing and pathogenesis. It is of further strategic research importance when considered with regard to human disease. Elevated CO2 (hypercapnia) contributes to poor prognosis in sleep apnoea, obesity and chronic obstructive pulmonary disorder and has been shown to confer chemoresistance in lung cancer cell lines. Understanding the molecular basis by which CO2 influences protein function in mammals is therefore crucial to the strategically important research area of public health in addition to providing fundamental knowledge of protein regulation by bioactive gases. Remarkably, we have almost no knowledge of direct CO2 targets in biological systems where it can form carbamates on the neutral N-terminal -amino- and lysine -amino-groups of proteins. So far, systematic identification of protein carbamylation sites was hindered by the reversible nature of the of carbamate modification making detection and quantification difficult. We have developed a tool that uses chemical proteomics to covalently trap CO2 on proteins, enabling for the first time proteomic analysis of this post-translational modification. Via this approach we demonstrated carbamylation is widespread in biology and identification of further protein-CO2 interactions represents an exciting, new and largely overlooked area of biochemistry that waits investigation.
The student will use a combination of mass spectrometry, chemical proteomics and molecular biology techniques to characterize CO2-binding proteins. The impact and influence of CO2-binding on protein function will be investigated through a mixture of molecular biology, cell biology and biochemistry techniques. The project will therefore offer a broad multi-disciplinary training opportunity. Additionally, the strategic partnership with AstraZeneca, a leading biopharmaceutical company, will expose the successful applicant to the industrial environment. The majority of the project will take place in the group of Martin Cann at the University of Durham and will include a minimum three-month placement at a UK AstraZeneca site.
You should have, or expect to obtain, a first or upper second class honours degree in a relevant subject and meet the eligibility criteria set out in the BBSRC guidelines. Funding is for four years at the standard BBSRC rate with an additional contribution from AstraZeneca.
The identification of carbon dioxide mediated protein post-translational modifications. Linthwaite VL, Janus JM, Brown AP, Wong-Pascua D,
O'Donoghue AC, Porter A, Treumann A, Hodgson DRW, Cann MJ. Nat Commun. (2018) Aug 6;9(1):3092. doi: 10.1038/s41467-018-05475-z.