Investigating the role of P2X7 receptor intracellular domains in cell signalling

Project Description

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 little about their interactions with other biomolecules, or which parts of them are involved in signalling pathways. 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. Recent work suggests that the ballast domain can bind to calcium-calmodulin, and that this may affect its conformation.

The focus of this project is to investigate the role of P2X7 intracellular domains in downstream signalling, using a combination of molecular modelling, site-directed mutagenesis, protein expression, protein purification, functional assays and direct structural studies. Particular focus will be given to understanding the role the ballast domain in coupling to intracellular signalling cascades.

How to apply: 

You can apply online – consideration is automatic on applying for a PhD in Biosciences

Please use our online application service at https://www.cardiff.ac.uk/study/postgraduate/research/programmes/programme/biosciences-phd-mphil-md

Please specify that you are applying for this particular project, the supervisor and source of funding.

Information on the application process can be found here

http://www.cardiff.ac.uk/study/postgraduate/applying

Academic criteria: Applicants should have obtained, or be about to obtain, a first or upper second-class UK honours degree, or the equivalent qualification gained outside the UK, Applicants with a lower second class will only be considered if they also have a Master’s degree. Please check the entry requirements of the home institution for each project of interest before completing an application. Academic qualifications are considered alongside significant relevant non-academic experience.

English requirements: If English is not your first language you will need to meet the English language requirements of the university that will host your PhD by the start of the programme. Please refer to the relevant university website for further information.