ArticleThe Journal of biological chemistry2010
Phosphorylation-induced conformational changes in the retinoblastoma protein inhibit E2F transactivation domain binding.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 102 papers.
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Who cites it
102 citing papers in PubMed.
- Chromatin association promotes UBR5-mediated degradation of Rb.bioRxiv : the preprint server for biology · 2026Article
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- The cell-permeable iron chelator M606 inhibits MYCN-driven neuroblastoma via an E2F3-mediated response.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Genetics and current research models of Mendelian tumor predisposition syndromes with ocular involvement.Progress in retinal and eye research · 2025Review
- Current and future therapies for small cell lung carcinoma.Journal of hematology & oncology · 2025Review
- Selective Up-Regulation of Tumor Suppressor Gene Retinoblastoma by Bisacridine Derivative Through Gene Promoter Quadruplex Structures for Cancer Treatment.International journal of molecular sciences · 2025Article
- Regulation of cell cycle in plant gametes: when is the right time to divide?Development (Cambridge, England) · 2025Review
- Developmental cues are encoded by the combinatorial phosphorylation of Arabidopsis RETINOBLASTOMA-RELATED protein RBR1.The EMBO journal · 2024Article
- Development of a rapamycin-inducible protein-knockdown system in the unicellular red alga Cyanidioschyzon merolae.Plant physiology · 2024Article
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- Comprehensive proteogenomic characterization of rare kidney tumors.Cell reports. Medicine · 2024Article
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- P53 and Rb Aberrations in Small Cell Lung Cancer (SCLC): From Molecular Mechanisms to Therapeutic Modulation.International journal of molecular sciences · 2024Review
- Deregulated kinase action in prostate cancer: molecular basis and therapeutic implications.Endocrine-related cancer · 2023Review
- Retinoblastoma Protein Is Required for Epstein-Barr Virus Replication in Differentiated Epithelia.Journal of virology · 2023Article
- The Four Homeostasis Knights: In Balance upon Post-Translational Modifications.International journal of molecular sciences · 2022Review
- Article
- Post-translational modifications on the retinoblastoma protein.Journal of biomedical science · 2022Review
- Understanding Retinoblastoma Post-Translational Regulation for the Design of Targeted Cancer Therapies.Cancers · 2022Review
42 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors.
Funding
Abstract
Inactivation of the retinoblastoma protein (Rb) through phosphorylation is an important step in promoting cell cycle progression, and hyperphosphorylated Rb is commonly found in tumors. Rb phosphorylation prevents its association with the E2F transcription factor; however, the molecular basis for complex inhibition has not been established. We identify here the key phosphorylation events and conformational changes that occur in Rb to inhibit the specific association between the E2F transactivation domain (E2F(TD)) and the Rb pocket domain. Calorimetry assays demonstrate that phosphorylation of Rb reduces the affinity of E2F(TD) binding approximately 250-fold and that phosphorylation at Ser(608)/Ser(612) and Thr(356)/Thr(373) is necessary and sufficient for this effect. An NMR assay identifies phosphorylation-driven conformational changes in Rb that directly inhibit E2F(TD) binding. We find that phosphorylation at Ser(608)/Ser(612) promotes an intramolecular association between a conserved sequence in the flexible pocket linker and the pocket domain of Rb that occludes the E2F(TD) binding site. We also find that phosphorylation of Thr(356)/Thr(373) inhibits E2F(TD) binding in a manner that requires the Rb N-terminal domain. Taken together, our results suggest two distinct mechanisms for how phosphorylation of Rb modulates association between E2F(TD) and the Rb pocket and describe for the first time a function for the structured N-terminal domain in Rb inactivation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.