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Capturing Membrane Protein Folding and Misfolding on the Ribosome

   Department of Chemistry

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  Prof P Booth, Dr E Reading  No more applications being accepted  Competition Funded PhD Project (UK Students Only)

About the Project

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 cells [1] .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 mechnaism of this process have yet to be elucidated [2,3.] 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 folding [4] . 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.

For informal enquires email: paula.booth(@)kcl.ac.uk; eamonn.reading(@)kcl.ac.uk

Group site: www.kcl.ac.uk/research/booth; www.ereadinglab.com/

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.

At King’s, we are deeply committed to embedding good equality and diversity practice into all of our activities so that the university is an inclusive, welcoming and inspiring place to study, regardless of age, disability, gender reassignment, marital status, pregnancy and maternity, race, religion, sex or sexual orientation.

Funding Notes

The studentships are funded for 4 years, with a stipend at the standard research council rate, which is presently £17,609 per annum including London Allowance, and cover the full cost of Home tuition fees. Income tax is not payable on the stipend.


[1]E. Reading et al Nature communications, 2020, 11, 5565.
[2]N. J. Harris & P. J. Booth Trends Biochem Sci, 2019, 44, 729.
[3]N. J. Harris et al Scientific reports, 2017, 7, 8021.
[4]G. A. Pellowe et al Biochemistry, 2020, 59, 2764.
[5] E. Reading et al Angew Chem Int Ed Engl, 2017, 56, 15654
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