Bifunctional degrader molecules also known as Proteolysis Targeting Chimeras (PROTACs) and the mechanistically related monovalent degraders (for example auxin, lenalidomide and indisulam) work by co-opting an E3 ubiquitin ligase to act upon a neo-substrate protein. Formation of a ternary complex species between the E3 ligase, the degrader molecule and the target protein leads to the latter being ubiquitinated and subsequently degraded by the proteasome.
This project is offered as part of the University of Dundee 4-year MRC DTP Programme “Quantitative and Interdisciplinary approaches to biomedical science”.
Phosphorylation is a major posttranslational modification whose disruption is linked to multiple human diseases. Our lab has recently found a link between the Parkinson’s associated protein kinase PINK1 and a subset of Rab GTPases. This project will employ state-of-the-art methods to uncover the regulation of Rabs by PINK1 in cells .
The project will lead to training in a wide array of technologies including mass spectrometry and biochemistry. The lab is also linked to the EMBO network and the student will also benefit from training opportunities in Europe during their studies.
Recent work from our group has shown the value in analysing paralogous gene families to boost the functional signal in data from DNA sequencing human exomes and genomes at the population level (MacGowan et al, 2017). The signal is especially strong in families of protein repeats such as TPRs, Ankyrins, HEAT and Armadillo and our recent collaborative research has shown how population genetics data can be used to select variants least likely to perturb function (Llabrés et al, 2019). The project will extend these principles to a wider range of protein families important in disease.
Ubiquitination is a posttranslational modification that regulates all aspects of physiology and aberrant ubiquitination has been implicated with numerous diseases. Ubiquitination is typically considered a posttranslational modification of lysine residues but it is emerging that non-lysine ubiquitination is intrinsic to mammalian biology. This project will use a multidisciplinary approach to understand the cellular function of non-lysine ubiquitination.