Summary
The cyclin-dependent kinases Cdk4 and Cdk6 form complexes with D-type cyclins to drive cell proliferation. A well-known target of cyclin D-Cdk4,6 is the retinoblastoma protein, Rb, which inhibits cell cycle progression until its inactivation by phosphorylation. However, the role of cyclin D-Cdk4,6 phosphorylation of Rb in cell cycle progression is unclear because Rb can be phosphorylated by other cyclin-Cdk complexes and cyclin D-Cdk4,6 complexes have other targets that may drive cell division. Here, we show that cyclin D-Cdk4,6 docks one side of an alpha-helix in the C-terminus of Rb, which is not recognized by cyclins E, A, and B. This helix-based docking mechanism is shared by the p107 and p130 Rb-family members across metazoans. Mutation of the Rb C-terminal helix prevents phosphorylation, promotes G1 arrest, and enhances Rb’s tumor suppressive function. Our work conclusively demonstrates that the cyclin D-Rb interaction drives cell division and defines a new class of cyclin-based docking mechanisms.
