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Deciphering the role of the intracellular domains of P2X7 in coupling to downstream signalling


   Cardiff School of Biosciences


About the Project

P2X7 receptors are ion channels that are found on the surface of immune cells, where they respond to the binding of extracellular ATP, a damage signal released by dying cells in infection and injury. ATP binding to P2X7 receptors leads to calcium influx and initiates a downstream signalling cascade, resulting in the formation of large pores in the plasma membrane, changes in cell shape, protein secretion, kinase activation and changes in gene expression. Both ion channel function and downstream signalling are highly regulated by the 30 amino-acid N-terminal and 240 amino-acid C-terminal intracellular domains of the receptor (NTD and CTD), at least in part via interaction with lipids in the plasma membrane, but we know very little about their interactions with other biomolecules, or which parts of them are involved in signalling pathways. The recent publication of the cryoEM structure of full-length rat P2X7 shows that both the NTD and the cysteine-rich N-terminal portion of the CTD (C-Cys anchor) are palmitoylated, anchoring these domains to the inner leaflet of the plasma membrane, and that the C-terminal portion of the CTD (ballast) forms a globular domain containing binding sites for dinuclear zinc and GDP/GTP, raising intriguing questions about its potential function.

The focus of this project will be to understand the role of P2X7 intracellular domains in downstream signalling, using a combination of molecular modelling, site-directed mutagenesis, protein expression, protein purification and functional assays. Particular focus will be given to understanding the role of lipids in regulating receptor function, and the role of the ballast domain in coupling to intracellular signalling cascades. We will also attempt to express and purify full-length P2X7 receptors (or their intracellular domains) for 3D-structure study using cryoEM or X-ray crystallography.


References

Successful applicant will need to provide bench fees of £15,000 per annum.

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