Phosphorylation-induced unfolding regulates p19(INK4d) during the human cell cycle

Cell cycle progression is tightly controlled in healthy organisms and often perturbed in human diseases, including, most prominently, many forms of cancers. Cyclin-dependent protein kinases and their inhibitors, such as p19(INK4d), regulate the different stages of the cell cycle. Here, we demonstrate how sequential phosphorylation of p19(INK4d) at two sites first destabilizes and then unfolds the N-terminal half of the protein, which dissociates its cyclin-dependent protein kinase-inhibitory complex and primes p19(INK4d) for cellular degradation. Our results define a structural mechanism by which phosphorylation-induced protein unfolding controls a key step in cell cycle progression.