Pseudokinases in neurodevelopment and disease

Pseudokinases are enigmatic proteins that evolved such that they retained the evolutionarily conserved kinase-like fold but lost key residues required for substrate phosphorylation. Pseudokinases have unique functions ranging from altered enzymatic ability, modulation of other protein kinases, and acting as scaffolds or substrate sponges. Nowhere perhaps is this functional diversity more evident than the seemingly myriad roles of pseudokinases in brain development. Not surprisingly, mutations in pseudokinases are associated with several clinically significant neurodevelopmental disorders. Here, we review 5 such pseudokinases, their known functional roles in brain development, disease association, and the unanswered questions that remain. Addressing the unexplored landscape of pseudokinases in neurological disorders holds promise of uncovering important insights into neuropathology and novel therapeutic targets. SIGNIFICANCE STATEMENT: Pseudokinases are understudied proteins that lack the catalytic ability to mediate phosphorylation, yet, they perform extraordinary and physiologically essential signaling functions. This review highlights the importance of pseudokinases in brain development and how their dysregulation leads to neurological disorders. Greater understanding of the structure, function, and regulation of pseudokinases is critical for the design of small molecules that can modulate their function.