Postdoctoral Research Assistant - MRC PPU - UOD1825

Postdoctoral research vacancy to understand why mutations in the protein kinase ALPK1 cause ROSAH syndrome MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee.

ROSAH is a disease that leads to blindness in young adults and the first disease shown to be caused by loss of specificity of an enzyme for its allosteric activator. We are seeking to appoint a highly motivated scientist to advance understanding of how ALPK1 mutation causes the disease and to develop the reagents and technologies needed to facilitate the develop of treatments to treat and/or prevent ROSAH syndrome.

The position is for 2.5 years and would be suitable for scientists with expertise in biochemistry, cell and molecular biology, and a strong interest and experience in studying protein phosphorylation, protein kinases, cell signalling and the development and characterisation of monoclonal antibodies..

Candidates must have a PhD and have at least one 1st authored paper published or accepted in a peer-reviewed journal. The position will be an opportunity for candidates to broaden their skillset by working in a well-funded lab using state- of-the-art technologies. Many of the scientists trained in this lab have subsequently gained an international reputation in the field of cell regulation.

Your priorities will include:

• Development and exploitation of monoclonal antibodies as biomarkers for the ALPK1 signalling pathway, and ROSAH syndrome
• Elucidation of unsolved aspects of the ALPK1 signalling network
• Preparation of results for publication
• Interacting with other lab members and collaborators
• Maintenance of meticulous lab records

For further information about this position please contact Sir Philip Cohen (p.cohen@dundee.ac.uk). To find out more about the MRC Protein Phosphorylation and Ubiquitylation Unit please visit https://www.ppu.mrc.ac.uk.

The closing date for applications is January 6th 2025. The successful applicant will receive a contract for a fixed term period of 2.5 years

Background

ALPK1 is normally activated by the bacterial metabolites ADP heptose or UDP-heptose. This enables ALPK1 to phosphorylate the adaptor protein TIFA, which induces it’s polymerisation to TIFAsomes, which recruit and activate signalling molecules that trigger the production of inflammatory mediators needed to combat the bacterial infection. ROSAH syndrome is caused by particular mutations in ALPK1. In most affected individuals threonine 237 of ALPK1 is mutated to methionine, but two other disease-causing variants have been identified in which tyrosine 254 is changed to cysteine or serine277 is changed to phenylalanine. The Cohen lab recently discovered that the Thr237Met and Ser277Phe mutations alter the specificity of ALPK1 for bacterial ADP-heptose and UDP-heptose and allow it to also be activated by related nucleotide sugars present in human cells, such as UDP-mannose and ADP-ribose. Consequently, the ALPK1 signalling pathway is switched on chronically in human cells in the absence of bacterial infection, leading to the eye inflammation that cause blindness. The Cohen lab have published three papers and a review on this topic, which can be accessed by clicking the following links:-

https://pmc.ncbi.nlm.nih.gov/articles/PMC9704527/pdf/BCJ-479-2195.pdf https://doi.org/10.1073/pnas.2313148120 https://www.biorxiv.org/content/10.1101/2024.09.13.612837v1

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