Cyclin D-Cdk4,6 Drives Cell-Cycle Progression via the Retinoblastoma Protein's C-Terminal Helix
| Autor: | Topacio, Benjamin R, Zatulovskiy, Evgeny, Cristea, Sandra, Xie, Shicong, Tambo, Carrie S, Rubin, Seth M, Sage, Julien, Kõivomägi, Mardo, Skotheim, Jan M |
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| Rok vydání: | 2019 |
| Předmět: |
Protein Conformation
kinase Cdk Retinoblastoma-Like Protein p107 environment and public health Retinoblastoma Protein Medical and Health Sciences S Phase Rare Diseases cyclin E2F Cyclins Cyclin D Humans Protein Interaction Maps Phosphorylation Rb Cell Proliferation cell-cycle regulation G1/S Cell Cycle alpha-Helical G1 Phase Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinase 6 Biological Sciences Molecular Docking Simulation enzymes and coenzymes (carbohydrates) Crk-Associated Substrate Protein docking biological phenomena cell phenomena and immunity Protein Binding Developmental Biology |
| Zdroj: | Molecular cell, vol 74, iss 4 |
| Popis: | 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 theRb 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. |
| Databáze: | OpenAIRE |
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