Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1

We present evidence that phosphorylation of the C-terminal region of Rb by Cdk4/6 initiates successive intramolecular interactions between the C-termi nal region and the central pocket. The initial interaction displaces histon e deacetylase from the pocket, blocking active transcriptional repression b y Rb. This facilitates a second interaction that leads to phosphorylation o f the pocket by Cdk2 and disruption of pocket structure. These intramolecul ar interactions provide a molecular basis for sequential phosphorylation of Rb by Cdk4/6 and Cdk2. Cdk4/6 is activated early in G1, blocking active re pression by Rb. However, it is not until near the end of G1, when cyclin E is expressed and Cdk2 is activated, that Rb is prevented from binding and i nactivating E2F.