Cyclin D-Cdk4,6 drives cell cycle progression via the retinoblastoma protein’s C-terminal helix

Topacio, B. R.; Zatulovskiy, E.; Cristea, S.; Xie, S.; Tambo, C. S.; Rubin, S. M.; Sage, J.; Koivomägi, M.; Skotheim, J. M.

doi:10.1101/397448

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bioRxiv · 10.1101/397448

Cyclin D-Cdk4,6 drives cell cycle progression via the retinoblastoma protein’s C-terminal helix

Topacio, B. R.·Zatulovskiy, E.·Cristea, S.·Xie, S.·Tambo, C. S.·Rubin, S. M.·Sage, J.·Koivomägi, M.·Skotheim, J. M.

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Abstract

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 Rbs 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.

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Topacio, B. R., Zatulovskiy, E., Cristea, S., Xie, S., Tambo, C. S., Rubin, S. M., Sage, J., Koivomägi, M., Skotheim, J. M.. 2018-08-21. Cyclin D-Cdk4,6 drives cell cycle progression via the retinoblastoma protein’s C-terminal helix. https://doi.org/10.1101/397448

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