Shining a light on dark and gloomy kinases

Event details

Abstract

While protein kinases have been studied for decades and their catalytically-dead counterparts – the pseudokinases – for ~20 years, approximately one-third of the human kinome remain understudied and have been termed “dark” kinases. Our group has set out to demystify these understudied proteins through detailed studies of what they look like, where they act in cells, their biological functions, and how these are perturbed in disease.

Here, I will present our template for defining these functions – our program of work to understand the regulation and execution of necroptotic cell death by the Mixed lineage kinase domain-like (MLKL) pseudokinase, and the role of dysregulation of necroptosis in human disease. MLKL was implicated as the key effector in the programmed necrosis (or necroptosis) cell death pathway in 2012. This pathway has ancestral origins in innate immunity, but it is its dysregulation, such as in inflammatory diseases, that has attracted enormous interest as a therapeutic target. We have dissected the chronology of events in this pathway using novel tools, structural biology, biochemistry, microscopy, proteomics, mouse disease models and analysis of biopsies from patients with Inflammatory Bowel Disease (IBD).

By applying the same principles to dark (pseudo)kinases, we have been able to attribute biological functions and uncover some cool and unexpected mechanisms of kinase regulation. Here, I will present other examples, such as our work on the dark kinase, Protein Serine Kinase H1 (PSKH1). Through detailed biochemical studies, we have unveiled novel mechanisms by which kinase activity can be regulated, as well as how perturbed catalytic activity or interactions can lead to disease.