Structure, function and molecular interaction studies of membrane proteins important in mitochondrial energy metabolism

CRICHTON_U23CASE

This is an exciting opportunity to study the mitochondrial Uncoupling Proteins (UCPs), which are a group of membrane proteins that impact on cellular energy metabolism.

UCP1 occurs in specialised brown fat of mammals, where it acts to uncouple the process of oxidative phosphorylation in mitochondria to release energy as heat instead of making ATP.

Activity of the protein helps protect against cold temperatures, but may also may help combat metabolic disease in humans. The related proteins, UCP2- 5, occur in various other tissues but are not well understood despite being implicated in metabolic disorders, inflammation, ischemic shock, cancer and aging.

This project will focus on determining the core properties of UCP proteins to understand structure function relations and their biochemical roles, taking advantage of our advances in purifying and studying the molecular nature of UCP1.

The research will cover a breadth of biochemical and molecular biology techniques applicable to membrane proteins (e.g. recombinant protein production and purification, chromatography methods, liposome reconstitution/transport assays, mutagenesis), including approaches to investigate membrane protein ligand binding and protein-protein interactions (e.g. protein thermostability shift anaysis, Surface Plasmon Resonance and Fluid Flow-Induced Dispersion Analysis).

The studies include 3-12 months on placement with our non-academic partner, Peak Proteins Ltd, to provide complementary technological input and training to support the studies.

The successful candidate will be supervised by Dr Paul Crichton at the Biomedical Research Centre (BMRC), where they will benefit from state-of-art-facilities and an excellent research environment provided by the Schools of Medicine and Biological Sciences, as well the surrounding Norwich Research Park.

As well as training and wider experience provided by our non-academic partner, the student will also have exchange opportunities with our national and international collaborators. They will be further supported by the many personal and professional development opportunities provided by the University.

References

Nicholls DG, Mitochondrial proton leaks and uncoupling proteins Biochim Biophys Acta Bioenerg (2021) 1862:148428.

Bouillaud F, Alves-Guerra MC, Ricquier D. UCPs, at the interface between bioenergetics and metabolism (2016) Biochim Biophys Acta 1863:2443-56.

Crichton PG, Lee Y, Kunji. ER The molecular features of uncoupling protein 1 support a conventional mitochondrial carrier-like mechanism (2017) Biochimie 134:35-50.

Cavalieri R, Hazebroek MK, Cotrim CA, Lee Y, Kunji ERS, Jastroch M, Keipert S, Crichton PG. Activating ligands of Uncoupling protein 1 identified by rapid membrane protein thermostability shift analysis (2022) Mol Metab. 62:101526.

Lee Y, Willers C, Kunji ER, Crichton PG. Uncoupling protein 1 binds one nucleotide per monomer and is stabilized by tightly bound cardiolipin. (2015) Proc Natl Acad Sci U S A. 112:6973-8.0