Co-chaperone/Antioxidant Interactions in Cancer

Impaired protein quality control, in the crowded cellular environment, is associated with a wide range of diseases, including cancer. A greater understanding of the mechanisms by which co-chaperones, such as SGTA (Small, Glutamine-rich, Tetratricopeptide repeat protein Alpha), operate, may enable the development of innovative new strategies for targeting these pathologies. In prostate cancer cells, our collaborator has recently identified a novel interaction between SGTA and a complex which combats oxidative stress, is directly implicated in cancer and may serve to counteract otherwise lethal levels of reactive oxygen species.

A full understanding of SGTA has thus far remained elusive despite its importance for numerous cellular roles, many of which link with disease and, most pertinently now, for its interaction with a protein from SARS-CoV. We propose to structurally and functionally characterise the SGTA/antioxidant complex using an integrative structural approach [1] and investigate its role in lipophagic flux in cancer using RNAi, cell-based methodology for exploring lipid composition [2,3] in concert with mass spectrometry. It is hoped that X-ray crystallography and/or cryo-electron microscopy (EM) can be used to produce atomic-resolution structures of the proteins bound together. Native mass-spectrometry (MS) and hydrogen-deuterium exchange (HDX) will provide information on the motions and oligomeric states of the complexes. This studentship will be a great opportunity for the right candidate to apply these methods to a protein of high biological importance with a view to understanding the molecular basis of cancer. The insights gained from the structural experiments will shed light on the native function of the two proteins, whilst also informing on the likely effects of structural and lipid perturbations and how they tie into disease.

This project is highly interdisciplinary and integrative particularly exploiting the respective expertise of the two PIs in biophysics/structural biology and lipid chemical biology to achieve molecular level information about this complex and its role in cancer. The PhD student will drive the direction of the project in accordance with their interests and background with guidance from both supervisors. The student will attend group meetings as well as departmental/college seminars. They will have the opportunity to visit the collaborator lab in Texas, present their results at national meetings and at an international conference.

For informal enquiries email: rivka.isaacson(@)kcl.ac.uk; ulrike.eggert(@)kcl.ac.uk

Group Site: www.kcl.ac.uk/research/isaacson www.kcl.ac.uk/lsm/research/divisions/randall/research/sections/motility/eggert/index.aspx,

Application Procedure

Send your CV and a research statement to PGR-chemistry(@)kcl.ac.uk

Your research statement must detail:

1. Your previous research experience (final year projects, summer placements, year in industry etc).
2. Why you want to do a PhD and why you chose this programme

Complete an online application on the King’s College myApplication system at apply.kcl.ac.uk/

1. Register a new account/login
2. Once logged in, select Create a new application
3. Enter ‘Chemistry Research MPhil/PhD (Full-time/Part-time)' under Choose a programme. Please ensure you select the correct mode of study.

 CV submission and online application MUST both be completed by the deadline.

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