STRUCTURE OF THE CYCLIN-DEPENDENT KINASE INHIBITOR P19(INK4D)

In cancer, the biochemical pathways that are dominated by the two tumo ur-suppressor proteins, p53 and Rb, are the most frequently disrupted. Cyclin D-dependent kinases phosphorylate Rb to control its activity a nd they are, in turn, specifically inhibited by the Ink4 family of cyc lin-dependent kinase inhibitors (CDKIs) which cause arrest at the G1 p hase of the cell cycle. Mutations in Rb, cyclin D1, its catalytic subu nit Cdk4, and the CDKI p16(Ink4a), which alter the protein or its leve l of expression, are all strongly implicated in cancer. This suggests that the Rb 'pathway' is of particular importance(1). Here we report t he structure of the p19(Ink4d) protein, determined by NMR spectroscopy (2-4). The structure indicates that most mutations to the p16(Ink4a) g ene, which result in loss of function, are due to incorrectly folded a nd/or insoluble protein(5). We propose a model for the interaction of Ink4 proteins with D-type cyclin-Cdk4/6 complexes that might provide a basis for the design of therapeutics against cancer.