Cyclin D-Cdk4,6 Drives Cell-Cycle Progression via the Retinoblastoma Protein's C-Terminal Helix

Mol Cell. 2019 May 16;74(4):758-770.e4. doi: 10.1016/j.molcel.2019.03.020. Epub 2019 Apr 11.


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.

Keywords: Cdk; E2F; G1/S; Rb; cell-cycle regulation; cyclin; docking; kinase; phosphorylation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Cycle / genetics
  • Cell Proliferation / genetics*
  • Crk-Associated Substrate Protein / genetics
  • Cyclin D / chemistry
  • Cyclin D / genetics*
  • Cyclin-Dependent Kinase 4 / chemistry
  • Cyclin-Dependent Kinase 4 / genetics
  • Cyclin-Dependent Kinase 6 / chemistry
  • Cyclin-Dependent Kinase 6 / genetics
  • Cyclins / genetics
  • G1 Phase / genetics
  • Humans
  • Molecular Docking Simulation
  • Phosphorylation / genetics
  • Protein Binding / genetics
  • Protein Conformation, alpha-Helical / genetics
  • Protein Interaction Maps / genetics*
  • Retinoblastoma Protein / chemistry
  • Retinoblastoma Protein / genetics*
  • Retinoblastoma-Like Protein p107 / genetics
  • S Phase / genetics


  • BCAR1 protein, human
  • Crk-Associated Substrate Protein
  • Cyclin D
  • Cyclins
  • Retinoblastoma Protein
  • Retinoblastoma-Like Protein p107
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6