Lab Focus: Natural an engineered immune receptors. 

Each of our bodies contain trillions of cells that work together to make up a human and each and every one of those cells needs to coordinate with its neighbours to know what to do and when.  Many of these external cues are sensed by receptors that sit at the surface of cells and transmit information from the outside of the cell to the interior causing cell behaviour to change depending on the environmental changes in any given instant. The Call lab studies these receptors to understand how they are built, how they work and how we might redesign them to give cells new functions.

We are interested in understanding:

1. How these receptors do their work as biochemical translators of information;
2. What happens when they don’t function correctly, for example cancer, immunodeficiency and other blood diseases; and
3. How we can use this knowledge to build better custom sensors for adoptive cell therapies such as chimeric antigen receptor (CAR) T-cell immunotherapy.

Research interest

We have a particular focus on how the transmembrane domains of receptors contribute to the structure and function of immune-signalling complexes. These are not mere anchors for extracellular and intracellular domains, but provide a unique platform for molecular interactions and represent the only direct physical link between ligand-binding and signalling domains across the cell barrier.

To understand how receptors are activated and the interactions the make with other proteins we are using deep-mutational scanning to uncover mechanistic insights, such as which areas of the protein are susceptible to disease-causing mutations and how to these relate to the natural function of the receptor. A major focus in recent years has been the development (with computational protein design collaborators) and structural characterisation (by x-ray crystallography) of synthetic transmembrane domains as tools to control the structures and activities of engineered receptors such as chimeric antigen receptors for CAR T-cell immunotherapies.

During the pandemic we pivoted some of our research towards understanding how SARS-CoV-2 will respond to therapeutics targeting the viral proteases required for SARS-CoV-2 replication. Our research will predict viral escape mutants before they are observed in the clinic and provide deeper mechanistic insight into Mpro and PLpro function.