- Wellcome Trust Senior Research Fellow & Professor of Structural Biology
- Areas of expertise
- Ubiquitin; cell signalling; immune response; DNA damage; metabolism
- 8.107 Astbury
- Biological Sciences
- Mollecular and Cellular Biology
Our laboratory studies how signalling networks are regulated by ubiquitin. We use structural biology, enzymology and biochemical and biophysical assays to elucidate the mechanism by which multi-subunit deubiquitylases (DUBs) function.
We identified the metabolic enzyme SHMT2 as the first endogenous inhibitor of DUB activity. We also showed that SHMT2 and vitamin B6 regulate interferon receptor degradation, thus impacting interferon signalling and inflammation.
We also dedicate a major effort in identifying DUB inhibitors as tool compounds to understand biological function and as potential leads for future therapeutics.
Current major projects
- Understanding DUB selectivity and their physiological regulation
- Understanding DUB allosteric activation
- Identification of DUB inhibitors as chemical biology tools and potential therapeutics
Detailed research programme
Metabolic control of immune signaling and regulation of deubiquitylating enzymes
Our immune system responds to metabolic changes with profound impact in inflammatory signaling. However, precise molecular mechanisms of how these signaling events are controlled are rare. Interferon receptors IFNAR1 and 2 are substrates of the BRISC deubiquitylating complex and BRISC is required for sustained immune signaling. We revealed a fascinating molecular mechanism that connected BRISC with a metabolic enzyme called serine hydroxymethyltransferase 2 (SHMT2). SHMT2 regulates one-carbon transfer reactions that are essential for amino acid and nucleotide metabolism, and uses pyridoxal-5′-phosphate (PLP) as a cofactor. SHMT2 also promotes inflammatory cytokine signaling by interacting with BRISC. Our laboratory elucidated the structure of the BRISC-SHMT2 10-subunit complex by cryo-EM and revealed how PLP regulates SHMT2 oligomerization and therefore BRISC function (Walden et al., Nature 2019). These studies uncovered new mechanistic insights on how DUBs are regulated in cells and how small metabolites like PLP regulate immune signaling