Membrane proteins underlie virtually all physiological processes. These proteins reside in cell membranes and govern all transport and communication in and out of cells. Consequently, membrane proteins dominate drug targets and are central to antibiotic resistance as they function as multi-drug transporters that pump antibiotics out of cells1 .This project aims to capture membrane proteins midway through their natural synthesis to assess a) how they fold to their correct structure and b) when mistakes occur that lead to misfolding. Membrane protein misfolding is increasingly being linked with disease, as for example in cyctic fibrosis and retina degeneration. The advances made during this project will be crucial to devise strategies to rectify the misfolding mistakes that occur during the synthesis of these proteins.
The correctly folded structure of a protein is vital for biological function and healthy cells. Proteins fold as their genetic code is being translated by ribosomes, but the structural details and mechanism of this process have yet to be elucidated2, 3. This project will involve trapping a membrane protein as it folds on the ribosome and inserts into a cell membrane. The structure of this trapped intermediate will be studied at near atomic resolution by state-of-the-art cryo electron microscopy (cryoEM).
We have already successfully captured nascent membrane proteins bound to the ribosome (“ribosome nascent chains”, RNCs) midway through their folding4 . This involves a novel method using a polymer (diisobutylene-maleic acid, DIBMA) to extract the RNC directly from the cell membrane in its native membrane-lipid environment, forming a RNC-lipid polymer nanodisc. Furthermore, these nanodisc samples have enabled us to obtain preliminary cryoEM data on these RNCs.
The PhD research will involve a range of chemical biology, physical chemistry and biophysical methods alongside molecular biology. As well as cryoEM there will be opportunities to test methods to probe the dynamics of the folding protein, for example using hydrogen-deuterium exchange mass spectrometry (HDX-MS)5 . This emerging technique monitors flexible regions of the protein as they exchange hydrogen for deuterium. Changing patterns of this hydrogen-deuterium exchange signature could highlight areas that misfold.
The student will work jointly between the neighbouring labs of Booth and Reading at King’s, with additional experiments being undertaken in the supervisors’ satellite laboratories at the Francis Crick Institute where the cryoEM is performed. Our two groups already work extensively together.
Essential criteria:
Prospective candidates should have a 1st or 2:1 M-level qualification in Chemistry, or a related subject.
Candidates should be able to demonstrate an aptitude for multidisciplinary research, the ability to work collaboratively in a diverse research environment as will a track-record of problem-solving and independence.
Application Process
1. Send your CV and cover letter to [Email Address Removed]
2. Complete an online application on the King’s College myApplication system (https://apply.kcl.ac.uk/):
a. Register a new account/login
b. Once logged in, select Create a new application
c. Enter ‘Chemistry Research MPhil/PhD (Full-time/Part-time)' under Choose a programme. Please ensure you select the correct mode of study.
3. CV submission and online application MUST both be completed by the deadline.
All relevant information regarding eligibility, including academic and English language requirements, is available from the online prospectus.
The deadline for applications is 15th June 2021. References must be submitted by the 21st June. We aim to hold interviews in late June/early July. If you require support with the application process, please contact the Chemistry Postgraduate Administrator Cairn Macfarland [Email Address Removed]