Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 17, Issue 9, Pages 1051-U3Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.1868
Keywords
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Funding
- US National Institute of Child Health and Human Development
- Canadian Institutes of Health Research [MOP89765]
- US National Institutes of Health [R01CA132685, T32GM008646]
- Canadian Institutes of Health Research
- CaRTT
- Santa Cruz Cancer Benefit Group
- Canadian Cancer Society
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The phosphorylation state and corresponding activity of the retinoblastoma tumor suppressor protein (Rb) are modulated by a balance of kinase and phosphatase activities. Here we characterize the association of Rb with the catalytic subunit of protein phosphatase 1 (PP1c). A crystal structure identifies an enzyme docking site in the Rb C-terminal domain that is required for efficient PP1c activity toward Rb. The phosphatase docking site overlaps with the known docking site for cyclin-dependent kinase (Cdk), and PP1 competition with Cdk-cyclins for Rb binding is sufficient to retain Rb activity and block cell-cycle advancement. These results provide the first detailed molecular insights into Rb activation and establish a novel mechanism for Rb regulation in which kinase and phosphatase compete for substrate docking.
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