The Kulathu lab is interested in understanding the molecular mechanisms by which posttranslational modifications mediate signal transduction. The innate immune response is the first line of defence against bacteria, viruses and parasites. When innate immune receptors are triggered they lead to the formation of a large oligomeric signalling complex called the Myddosome. Within the Myddosome, the IRAK kinases are activated to trigger a signalling cascade that culminates in the expression and secretion of cytokines that shape the immune response to invading pathogens. There are 4 IRAK kinases expressed in humans, two of which (IRAK2 and IRAK3) lack key catalytic residues and are therefore dead kinases or pseudo-kinases. The aim of this project will be to understand the molecular mechanisms by which these dead kinases regulate immune signalling. This project will build on recently published work (see Lange et al, Structure 2020), and will utilize protein biochemistry, cryo-electron microscopy and X-ray crystallography to define how IRAK kinases are activated and regulated. This project has the potential to reveal fundamental principles underlying the activation and regulation of innate immune signalling, and how they could be modulated to treat inflammatory diseases such as arthritis, atherosclerosis, systemic lupus erythematosus and psoriasis.