title: Structural basis for the recognition of the E2F transactivation domain by the retinoblastoma tumor suppressor.
abstract: Repression of E2F transcription activity by the retinoblastoma (Rb) tumor suppressor through its interaction with the transactivation domain of the E2F transcription factor is one of the central features of G1/S arrest in the mammalian cell cycle. Deregulation of the Rb-E2F interaction results in hyperproliferation, lack of differentiation, and apoptosis, and can lead to cancer. The 2.2-A crystal structure of the Rb pocket complexed with an 18-residue transactivation-domain peptide of E2F-2 reveals that the boomerang-shaped peptide binds to the highly conserved interface between the A-box and the B-box of the Rb pocket in a bipartite manner. The N-terminal segment of the E2F-2 peptide in an extended beta-strand-like structure interacts with helices from the conserved groove at the A-B interface, whereas the C-terminal segment, which contains one 3(10) helix, binds to a groove mainly formed by A-box helices. The flexibility in the middle of the E2F-2 peptide is essential for the tight association of E2F to the Rb pocket. The binding of Rb to the E2F-2 peptide conceals several conserved residues that are crucial for transcription activation of E2F. We provide the structural basis for the Rb-mediated repression of E2F transcription activity without the requirement of histone-modifying enzymes.
authors.affiliation: National Creative Research Center for Structural Biology and Department of Life Science, Pohang University of Science and Technology, San 31, KyungBook, South Korea.
authors.forename: Changwook
authors.initials: C
authors.lastname: Lee
authors.forename: Jeong Ho
authors.initials: JH
authors.lastname: Chang
authors.forename: Hyun Sook
authors.initials: HS
authors.lastname: Lee
authors.forename: Yunje
authors.initials: Y
authors.lastname: Cho
mesh_terms: D018797:Cell Cycle Proteins; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050703:E2F2 Transcription Factor; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D020349:Surface Plasmon Resonance; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050703:E2F2 Transcription Factor; C493761:E2F2 protein, human; D010446:Peptide Fragments; D016160:Retinoblastoma Protein; D014157:Transcription Factors