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

University of Birmingham Department of Metabolism and Systems Science

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Prof D Calebiro Prof Stephen Hill No more applications being accepted

Birmingham United Kingdom

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

Where will I study?

University of Birmingham

For more than a century, the University of Birmingham has been pursuing and sharing knowledge through outstanding teaching and research. As a founding Russell Group member and the original ‘redbrick’ university, our high-quality teaching will help you take your career to the next level. We are of the country’s most consistently sought-after universities by the UK’s top graduate employers, and have been for the last decade. With a wealth of opportunities to choose from across study and research, Birmingham has one of the most extensive postgraduate course portfolios in the UK. Hosting an international community of more than 8000 staff and 38,000 students, you’ll work alongside world-leading academics in a diverse community.

Career overview

Professor Davide Calebiro studied Medicine in Milan and Stockholm, obtaining a Clinical Specialization in Endocrinology and Metabolic Diseases as well as a PhD in Molecular Medicine from the University of Milan. From 2009 to 2018, he led a research group at the Institute of Pharmacology and Bio-Imaging Center of Würzburg University, Germany. He joined the University of Birmingham in 2017, supported by a Birmingham Professorial Fellowship. In 2018, he was awarded a prestigious Wellcome Trust Senior Research Fellowship. Professor Calebiro is the Head of the Department of Metabolism and Systems Science and a Professor of Molecular Endocrinology. He is also a Wellcome Trust Senior Research Fellow and Co-Director of the Centre of Membrane Proteins and Receptors (COMPARE) at the Universities of Birmingham and Nottingham. His research team is multidisciplinary, comprising biologists, chemists, physicists, engineers, and computer scientists, focusing on G protein-coupled receptor (GPCR) signalling and its alterations in endocrine and metabolic diseases. His major scientific contributions include the discovery that GPCRs are active not only at the plasma membrane but also at intracellular sites, and that these receptors form dynamic nanodomains at the plasma membrane. He has published 80 research papers in prestigious scientific journals and serves on multiple panels and committees, including the Programme Committee of the Society for Endocrinology and the MRC Molecular & Cellular Medicine Board.

Research interests

Professor Davide Calebiro''s research focuses on the basic mechanisms of G protein-coupled receptor (GPCR) signalling and their alterations in endocrine and metabolic diseases. He leads a multidisciplinary team that develops and employs innovative optical methods, such as FRET and single-molecule microscopy, to directly observe signalling events in living cells with high spatiotemporal resolution. His significant contributions include the discovery that GPCRs are active not only at the plasma membrane but also at intracellular sites, and that these receptors form dynamic nanodomains by interacting with each other and other membrane proteins. The research aims to advance understanding of GPCR signalling mechanisms to develop innovative pharmacological therapies for endocrine and metabolic diseases. The group also investigates genetic alterations in GPCR signalling, identifying genetic causes of diseases such as cortisol-secreting adrenocortical adenomas.

G Protein-Coupled Receptor Signalling Endocrinology Metabolic Diseases Optical Methods FRET Single-Molecule Microscopy Spatiotemporal Resolution Dynamic Nanodomains Pharmacology Genetic Alterations Innovative Microscopy Methods Biosensors Quantitative Information Mathematical Approaches Cellular Mechanisms Pharmacological Therapies

View Professor Davide Calebiro's profile