Looking lively: emerging principles of pseudokinase signaling

Progress towards understanding catalytically 'dead' protein kinases - pseudokinases - in biology and disease has hastened over the past decade. An especially lively area for structural biology, pseudokinases appear to be strikingly similar to their kinase relatives, despite lacking key catalytic residues. Distinct active-and inactive-like conformation states, which are crucial for regulating bona fide protein kinases, are conserved in pseudokinases and appear to be es-sential for function. We discuss recent structural data on conformational transi-tions and nucleotide binding by pseudokinases, from which some common principles emerge. In both pseudokinases and bona fide kinases, a conforma-tional toggle appears to control the ability to interact with signaling effectors. We also discuss how biasing this conformational toggle may provide opportuni-ties to target pseudokinases pharmacologically in disease.

Automated summary

Progress has been made in understanding the role of pseudokinases in biology and disease over the past decade. Despite lacking key catalytic residues, pseudokinases show striking similarity to their kinase relatives. Recent structural data suggest that both pseudokinases and bona fide kinases maintain distinct conformational states, which play a crucial role in their function. Understanding and targeting the conformational toggle in pseudokinases could have implications for disease treatment.