Membrane proteins are essential for cell signalling, transport, and drug targeting, yet how they fold correctly as they are synthesised remains poorly understood. This fully funded PhD will investigate the cotranslational folding of membrane proteins, a fundamental process with important implications for understanding disease and protein misfolding.
This highly interdisciplinary and collaborative Leverhulme Trust funded project will combine native nanodisc technology, proteomics, lipidomics, and biophysical approaches to capture and study membrane bound ribosome nascent chain complexes from human cells. By analysing how nascent membrane proteins interact with lipids, chaperones, and the translation machinery, the work will reveal key mechanisms that govern membrane protein folding and membrane integration.
Additionally, surface enhanced infrared absorption spectroscopy (SEIRAS) will be used to monitor membrane protein folding in real-time during in vitro translation. By coupling cell-free expression with synthetic bilayers or nanodiscs, SEIRAS enables direct observation of structural changes as human nascent proteins fold and insert into membranes. This provides a powerful way to connect molecular interactions identified by multiomics approaches with dynamic folding behaviour. SEIRAS will be carried out alongside world-leading researchers at King’s College London (KCL).
The student will be primarily based in the Aston Institute for Membrane Excellence (AIME) and will work in newly established laboratories designed for membrane protein research. Training will include advanced methods in mass spectrometry, membrane biochemistry, and structural biology. The project will use state of the art instrumentation including the Orbitrap Ascend Tribrid mass spectrometer at AIME and SEIRAS at KCL.
Project objectives
- Produce snapshots of MPs folding on the ribosome and purify in their natural setting so we can study their physical properties.
- Understand the environment in which these MPs fold, using a mix of biochemical tests and advanced analytical techniques.
- Examine the MP intermediate structures closely to see how certain factors affect how they fold.
- Follow structural changes as they happen in real-time to better understand the process.
Supervisory team
- Dr Grant Pellowe (Primary Supervisor), Aston Institute for Membrane Excellence
- Dr Ivana Milic, (mass spectrometry), Aston Institute for Membrane Excellence
- Dr Alice Rothnie, (membrane proteins and native nanodiscs), Aston Institute for Membrane Excellence
- Prof. Paula Booth, (membrane proteins and SEIRAS), King’s College London
The project offers training in interdisciplinary approaches spanning cell biology, proteomics, lipidomics, and membrane biophysics, while maintaining strong collaborative links between Aston University and King’s College London, and would suit a student with a strong interest in molecular biology, biochemistry, structural biology or mass spectrometry.
References
- doi.org/10.1021/acs.biochem.0c00423
- doi.org/10.1016/j.bbamem.2019.07.007
- doi.org/10.1038/s41594-025-01676-5
- doi.org/10.1038/s41598-017-08522-9
Key words
Protein folding, membrane proteins, structural biology, mass spectrometry, ribosomes, nanodiscs.