Structure of the cyclin-dependent kinase inhibitor p19 super(Ink4d)

In cancer, the biochemical pathways that are dominated by the two tumour-suppressor proteins, p53 and Rb, are the most frequently disrupted. Cyclin D-dependent kinases phosphorylate Rb to control its activity and they are, in turn, specifically inhibited by the Ink4 family of cyclin-dependent kinase inhibitors (CDKIs) which cause arrest at the G1 phase of the cell cycle. Mutations in Rb, cyclin D1, its catalytic subunit Cdk4, and the CDKI p16 super(Ink4a), which alter the protein or its level of expression, are all strongly implicated in cancer. This suggests that the Rb "pathway" is of particular importance. Here we report the structure of the p19 super(Ink4d) protein, determined by NMR spectroscopy. The structure indicates that most mutations to the p16 super(Ink4a) gene, which result in loss of function, are due to incorrectly folded and/or insoluble protein. 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.