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Deciphering p53 signaling


Project Description

We are offering a fully-funded studentship for an outstanding PhD candidate who will produce and study PTM variants of p53 to deepen our understanding of the function and regulation of this key tumour suppressor protein.

Cells are continuously exposed to cytotoxic damage. Appropriate responses – ranging from cell cycle arrest all the way to controlled cell death – are a critical line of defence against the onset of cancer. A key regulator of these pathways is the tumour suppressor protein p53, which is frequently mutated in cancer (1). p53 itself is tightly regulated by post-translational modifications (PTMs). Despite their importance, the molecular details of how specific PTMs and their combinations control p53 activity remain elusive. This iCASE PhD project aims to fill this gap through a collaborative chemical biology/biophysics approach in the Müller and Politis Labs at KCL and Dr Sean Devenish at Fluidic Analytics.

The Müller lab has developed a strategy to access site-specifically modified p53 using protein semi-synthesis (manuscript in preparation). During the first year, you will receive training in our cutting-edge semi-synthesis methodology – a combination of chemical peptide synthesis and recombinant technology (for applications, see refs 2,3). In this way, you will prepare a panel of site-specifically modified p53 variants, and further develop semi-synthesis approaches to produce previously inaccessible p53 variants.
You will then characterize the biophysical effects of p53 PTMs using innovative approaches developed by Fluidic Analytics (4) and the Politis Lab (5). Large-scale structural and functional changes will be measured through DNA binding assays and diffusive sizing during a 4 months placement at Fluidic Analytics. The impact of PTMs on local structure and dynamics will be determined via Hydrogen-Deuterium Exchange coupled to Mass Spectrometry (Politis lab).

This project will provide unique training to the PhD student in cutting edge chemical biology, structural biology and microfluidics-based analytical biochemistry in academic and industrial settings. Moreover, the results will further our understanding of p53, how it integrates stress signals in the form of PTMs to prevent cancer, and how these mechanisms are distorted by cancer-associated p53 mutations.

Applications

Applications must be complete, including both references, by 24th Jan 2020

Funding Notes

Fully funded place including home (UK) tuition fees and a tax-free stipend in the region of £17,009. Students from the EU are welcome to submit an application for funding, any offers will be subject to BBSRC approval and criteria.

References

(1) Hafner, A et al. (2019) The multiple mechanisms that regulate p53 activity and cell fate. Nature Reviews Mol. Cell Biol. 20: 199.
(2) Müller, MM et al., (2016) A two-state activation mechanism controls the histone methyltransferase Suv39h1. Nature Chem Biol. 12: 188.
(3) Müller, MM and Muir, T. (2015) Histones: At the Crossroads of Peptide and Protein Chemistry. Chemical Reviews 115: 2296.
(4) Yates et al., (2015) Latent analysis of unmodified biomolecules and their complexes in solution with attomole detection sensitivity. Nature Chemistry, 7: 802.
(5) Ahdash, Z et al., (2019) HDX-MS reveals nucleotide-dependent, anti-correlated opening and closure of SecA and SecY channels of the bacterial translocon. eLife 8: e47402.

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