Investigating TNF-Alpha Multimerisation and Activation Mechanisms

Tumour necrosis factor-alpha (TNF-α) is a key cytokine in immune regulation and inflammation, existing as a transmembrane precursor that undergoes proteolytic cleavage to release a soluble form. Both membrane-bound and soluble TNF-α exert their effects by binding TNF receptors (TNFR1/2), initiating signalling cascades that regulate cell survival, apoptosis, and inflammation. However, the structural dynamics of TNF-α multimerization and its impact on receptor activation remain poorly understood.

This PhD project aims to dissect the molecular mechanisms governing TNF-α multimerization and its functional consequences on TNFR activation. Using biophysical techniques such as NMR and crystallography, along with cellular assays and computational modelling, the study will elucidate how TNF-α oligomerization influences receptor binding and downstream signalling. Understanding these processes could reveal novel therapeutic options for TNF-driven diseases, including autoimmune disorders and cancer. This project integrates structural biology, immunology, and drug discovery approaches to advance TNF-targeted therapeutics.

McMillan, D., Martinez-Fleites, C., Porter, J. et al. (2021) Structural insights into the disruption of TNF-TNFR1 signalling by small molecules stabilising a distorted TNF. Nat Commun 12, 582. doi.org/10.1038/s41467-020-20828-3

To apply please refer to our web page https://le.ac.uk/study/research-degrees/funded-opportunities/liscb

Enquiries to Dr Gareth Hall gh126@le.ac.uk