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.
We have used our intensive studies of the necroptotic cell death effector, the Mixed lineage kinase domain-like (MLKL) pseudokinase, over the past decade as a template for establishing a platform encompassing novel tools, structural biology, biochemistry, microscopy, proteomics, mouse disease models and analysis of biopsies from patients to illuminate the functions of understudied kinases.
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 illustrate how this platform can illuminate dark kinase function, as exemplified by our work on 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.