Jean-Paul Vincent & Ed Tate

 

A chemical biology approach to target protein lipidation in development and neurodegenerative disease

Joint Crick/Imperial College London position

NOTE:

Additional eligibility criteria apply to this position: applicants to this position will be expected to hold either a 4-year MSci degree (at 2.1 level or higher), or a 3-year undergraduate degree plus a Masters (MSc, MRes, etc.)  degree. Non-EU applicants are not eligible for the funding for this project.

Lipidation is a common post-translational modification that modulates the activity of intracellular proteins. Recently, a small number of lipidated extracellular proteins have been identified. One such class is the Wnt protein family, which activates a conserved signalling pathway required for development and stem cell maintenance. In the context of disease, Wnt plays a critical role in cell proliferation and stem cell maintenance, with dysregulation of Wnt signalling important in both proliferative (e.g. cancers) and degenerative (e.g. Alzheimer's Disease) diseases. During biosynthesis, palmitoleate is specifically appended to Wnts, and without this modification Wnts are poorly secreted and unable to activate downstream signalling. Recent ground-breaking work from the Vincent lab has shown that a deacylase called Notum inactivates Wnts in the extracellular space, providing a new paradigm for how lipidation can regulate signalling activity for secreted proteins. Targeting the activity of Notum could be used to boost Wnt signalling in a therapeutic setting, for example to increase stem cell proliferation or stimulate synaptogenesis in Alzheimer's Disease.

Our ability to study protein lipidation has undergone a transformation with the development of modern chemical biology approaches, an area in which the Tate group has made key advances. You will design and implement a rich array of chemical tools to address the pressing challenge of understanding the roles of reversible lipidation in protein secretion and signalling, and enable novel insights into Wnt lipidation and trafficking in both disease and normal development. These tools will range from activity-based probes for lipid processing enzymes, to probes which can capture lipidated proteins and their interacting partners in living system, and will be implemented in cultured cells and in whole tissues from animal models. Thanks to the use of orthogonal chemical tagging technologies developed by the Tate lab, these will be applied to imaging, detection and de novo discovery of active enzymes, substrates and interactors through chemical proteomics.

Talented and motivated students passionate about research in both chemistry and biology are invited to apply for this PhD position. The student will benefit from interactions with members of both research groups based at the Crick Institute, and members of the Tate group at Imperial College in the new Molecular Sciences Research Hub at the Imperial College White City campus. [1-5]

This is just one example of the sort of project that might be available in these research groups. The precise project will be decided on in consultation with the supervisors.

1. Kakugawa, S., Langton, P. F., Zebisch, M., Howell, S. A., Chang, T.-H., Liu, Y., Feizi, T., Bineva, G., O'Reilly, N., Snijders, A. P., Jones, E. Y. and Vincent, J.-P. (2015)
Notum deacylates Wnt proteins to suppress signalling activity.
Nature 519: 187-192. PubMed abstract

2. Thinon, E., Serwa, R. A., Broncel, M., Brannigan, J. A., Brassat, U., Wright, M. H., Heal, W. P., Wilkinson, A. J., Mann, D. J. and Tate, E. W. (2014)
Global profiling of co- and post-translationally N-myristoylated proteomes in human cells.
Nature Communications  5: 4919. PubMed abstract

3. Broncel, M., Serwa, R. A., Ciepla, P., Krause, E., Dallman, M. J., Magee, A. I. and Tate, E. W. (2015)
Multifunctional reagents for quantitative proteome-wide analysis of protein modification in human cells and dynamic profiling of protein lipidation during vertebrate development.
Angewandte Chemie International Edition  54: 5948-5951. PubMed abstract

4. Yamazaki, Y., Palmer, L., Alexandre, C., Kakugawa, S., Beckett, K., Gaugue, I., Palmer, R. H. and Vincent, J.-P. (2016)
Godzilla-dependent transcytosis promotes Wingless signalling in Drosophila wing imaginal discs.
Nature Cell Biology  18: 451-457. PubMed abstract

5. McGough, I. J. and Vincent, J.-P. (2016)
Exosomes in developmental signalling.
Development  143: 2482-2493. PubMed abstract