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 Rb phosphorylation by cyclin D-Cdk4,6 in cell-cycle progression is unclear because Rb can be phosphorylated by other cyclin-Cdks, and cyclin D-Cdk4,6 has other targets involved in cell division. Here, we show that cyclin D-Cdk4,6 docks one side of an alpha-helix in the Rb C terminus, 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 its 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 expands the diversity of known cyclin-based protein docking mechanisms.

细胞周期蛋白依赖性激酶 Cdk4 和 Cdk6 与 D 型细胞周期蛋白形成复合物以驱动细胞增殖。细胞周期蛋白 D-Cdk4,6 的一个众所周知的靶点是视网膜母细胞瘤蛋白 Rb，它抑制细胞周期进程，直到通过磷酸化失活。然而，Rb 被细胞周期蛋白 D-Cdk4,6 磷酸化在细胞周期进展中的作用尚不清楚，因为 Rb 可以被其他细胞周期蛋白-Cdks 磷酸化，并且细胞周期蛋白 D-Cdk4,6 还有其他参与细胞分裂的靶标。在这里，我们发现细胞周期蛋白 D-Cdk4,6 与 Rb C 末端的 α 螺旋一侧对接，而细胞周期蛋白 E、A 和 B 无法识别该一侧。这种基于螺旋的对接机制由 p107 和 p107 共享。 p130 跨后生动物的 Rb 家族成员。 Rb C 端螺旋的突变可阻止其磷酸化，促进 G1 期停滞，并增强 Rb 的肿瘤抑制功能。我们的工作最终证明了细胞周期蛋白 D-Rb 相互作用驱动细胞分裂并扩展了已知的基于细胞周期蛋白的蛋白质对接机制的多样性。