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  Single-molecule analysis of protein-protein interactions in GPCR clustering and internalisation


   Institute of Metabolism and Systems Research

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  Prof D Calebiro, Prof Stephen Hill  No more applications being accepted

About the Project

Closing date 31 March, unless filled beforehand

G protein-coupled receptors (GPCRs) mediate the effects of a large number of hormones and neurotransmitters, are implicated in several human diseases and are major drug targets. Despite long-standing efforts, the dynamics of the protein-protein interactions at the heart of GPCR signalling remain poorly understood, mostly due to technical limitations. To circumvent these limitations, our groups are developing advanced biophysical methods, such as single-molecule microscopy combined with single-particle tracking and fluorescence correlation spectroscopy (FCS), which enable us to directly visualise and analyse protein-protein interactions at the surface of living cells with unprecedented spatiotemporal resolution (Calebiro et al., PNAS 2013; Sungkaworn et al. Nature 2017; Briddon and Hill 2018).

In this project, the successful candidate will apply single-molecule microscopy and FCS to investigate the interactions occurring among GPCRs, -arrestins and the plasma membrane lipid bilayer. The results will be used to build a detailed dynamic model of the key events involved in GPCR desensitisation, clustering and internalisation. The successful applicant will join a vibrant, dynamic and internationally-recognised interdisciplinary team at the Universities of Birmingham and Nottingham. The project is one of six that have been funded through the Centre of Membrane Proteins and Receptors (COMPARE: http://www.birmingham-nottingham.ac.uk/compare/index.aspx) that focus on receptor clustering. The six studentships will form a doctoral training programme that will provide additional training and opportunities for collaboration.

Applications should include a letter explaining why this project is of interest to the applicant along with a CV and the names of two referees. They should be sent to BR-BN-COMPARE [Email Address Removed] by 31 March.

Funding Notes

Funded by COMPARE, fees and stipend at UK rates for UK and EU nationals.

References

Sungkaworn T, Jobin ML, Burnecki K, Weron A, Lohse MJ, Calebiro D (2017) Single-molecule imaging reveals receptor-G protein interactions at cell surface hot spots. Nature 550, 543-547

Briddon SJ and Hill SJ (2018) Studying GPCR pharmacology in membrane microdomains: Fluorescence Correlation Spectroscopy comes of age. Trends Pharmacol. Sci. (in press)

Godbole A, Lyga S, Lohse MJ, Calebiro D (2017) Internalized TSH receptors en route to the TGN induce local Gs-protein signaling and gene transcription. Nature communications 8, 443

Calebiro D, Rieken F, Wagner J, Sungkaworn T, Zabel U, Borzi A, Cocucci E, Zürn A, Lohse MJ (2013) Single-molecule analysis of fluorescently labeled G-protein-coupled receptors reveals complexes with distinct dynamics and organization. Proc. Natl. Acad. Sci. U. S. A. 110:743-748

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