Protein kinases are enzymes that attach phosphate to proteins, a process known as “phosphorylation”. Phosphorylation can change the shape of proteins and hence their ability to function, so that kinases are key controller enzymes that regulate almost every process in human cells. Many kinases have additional functions beyond phosphorylation, and some have even lost their ability to phosphorylate proteins altogether. These ‘inactive’ kinases are called ‘pseudokinases’, from the Greek word ‘pseudos’ (Engl. ‘false’). Pseudokinases often evolved unique ways to relay messages in the cell and to impact cellular processes. Our work focuses on the pseudokinase IRAK3, which belongs to the group of Interleukin-1 receptor associated kinases (IRAKs). The IRAKs are key players of the innate immune system, our body’s first line of defence against invading bacteria and viruses.

We report the first crystal structure of IRAK3, the detailed three-dimensional arrangement of atoms in the IRAK3 molecule. The structure provides us with new clues as to how IRAK3 works and what impact disease-associated mutations in IRAK3 have. We found that IRAK3 can attach itself to another IRAK3 molecule in a novel way never observed previously in other kinases. We found that alterations in IRAK3 that are more prevalent in asthmatics are clustered in a region of IRAK3 that we predict to be involved in attaching IRAK3 to the related family member IRAK4, suggesting that IRAK3 might control the activity of IRAK4. Our work lays the foundation to understand the function of IRAK3 as a potential drug target, and is an important first step towards the development of new medications for patients with asthma and other diseases of the innate immune system.

This work was funded by Medical Research Scotland and Janssen Pharmaceutica, a research division of Johnson and Johnson.

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