Apoptin is a small viral protein capable of inducing cell death selectively in cancer cells. Using a combination of protein semisynthesis and cell biological assays, we have collaboratively shown that Apoptin becomes phosphorylated in cancer cells, which activates the apoptin to disrupt the cytoskeleton and thereby promote cell death. This project builds on our discovery of apoptin’s mode of action and aims to fill in the mechanistic details using a multidisciplinary approach.
The key aims of the project are to fully identify the set of kinases that activate apoptin (Year 1), to chemically synthesise phosphorylated and/or fluorescently-labelled apoptin derivatives (Year 2) to delineate how phosphoApoptin interacts with the cytoskeleton through a multi-pronged cellular, biochemical and computational approach (Year 3). Finally, the project will explore whether the unique mechanism of apoptin activation allows transmission of phosphoApoptin, generated in cancer cells, to nearby bystander cells in a 3D tumour model (Year 4).
Summary and Outlook: Collectively, this project will provide mechanistic insights into how an anticancer protein selectively disrupts the cytoskeleton in its phosphorylated form, a development that would likely lead to a high impact publication. The resulting insights will provide a starting point for the design of next-generation anticancer peptides and proteins.
This project would suit candidates with a background in protein chemistry or cell biology and with a keen interest in acquiring interdisciplinary research skills at the interface of chemistry and biology. This project combines approaches across traditional scientific disciplines, building on the joint expertise of the supervisory team. The student will receive hands-on training in cell/cancer biology (Tavassoli lab), protein chemistry (Müller lab) and Molecular Dynamics (MD) simulations (Ulmschneider lab).