Our work is focused on understanding how proteins within cells interact, and how genetic mutations that perturb these interactions can cause disease.
We are particularly interested in interactions between proteins involved in cell signalling. The network of signalling proteins within cells can be likened to an electronic circuit. Our research is identifying the missing components in these ‘circuits’ and explaining how diseases are caused by defects in the circuit components.
By understanding how defective signalling causes disease, we aim to develop drugs to control the actions of defective components. In particular we are seeking to understand how signalling defects can lead to a range of diseases, including ischemia-reperfusion injuries, such as stroke and kidney injury, inflammatory bowel disease, muscular dystrophy and cancers.
We aim to understand how changes in our DNA lead to inflammatory diseases in patients with disease. Our work provides detailed insights into the underlying mechanisms that we can build on to develop drugs to counter debilitating diseases, like Crohn’s disease and ulcerative colitis.
Our work has illuminated the molecular mechanism by which the killer protein, MLKL, is activated by the upstream kinase, RIPK3, to induce a pro-inflammatory form of cell death called necroptosis. Using innovative tools and integrative methods, we have defined four critical regulated steps in MLKL’s activation, which we term “checkpoints” in the necroptosis signaling pathway.
More broadly, we have validated pseudokinases, like MLKL, as underappreciated, but critical, signalling molecules throughout nature. Pseudokinases comprise ~10% of our kinome, and through detailed study, we have described diverse functional mechanisms by which pseudokinases function in signalling pathways, and how these functions are disrupted in disease. These studies have unearthed pseudokinases as novel candidates for therapeutic targeting.
The pseudokinase, MLKL, is the terminal effector in the necroptosis cell death pathway. Our structural studies and development of MLKL-deficient laboratory models have enabled us to greatly advance mechanistic knowledge of this protein. Our ongoing work is directed toward understanding how MLKL kills cells following its activation by the upstream protein kinase, RIPK3, and the role of this pathway in causing inflammatory diseases and cancer. These studies are highly collaborative and draw upon in vivo biology, structural biology, molecular and cellular biology, biochemistry, chemical biology and proteomics approaches.
We have identified allostery, molecular switch, scaffolding and competition functions for pseudokinases from detailed structural and functional characterization. Many pseudokinases remain understudied and are considered members of the “dark kinome”. Ongoing work seeks to define the biological functions of these proteins, how they misfunction in disease, and establish their candidacy as drug targets to counter human diseases, especially inflammatory and proliferative diseases. Our work is highly collaborative, with integration of in vivo biology, structural biology, molecular and cellular biology, biochemistry, chemical biology and proteomics to dissect their functions.
Smchd1 is a poorly understood protein comprising an N-terminal ATPase and C-terminal hinge domain. Our recent studies have sought to understand the biological functions (in collaboration with Prof Marnie Blewitt) and structures (in collaboration with Prof Peter Czabotar) of the component domains with a view to understanding its pleiotropic roles as a tumour suppressor, in X chromosome inactivation and gene imprinting.