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Creb Binding Protein

Creb Binding Protein. Ahmed Sadek. What is CBP?. CBP is a coactivator. TFs: CREB and CFos Highly related to p300. Discovered with CREB Integrator of STP. Transcription Factors/Coactivators. Coactivators needed for transcription factors TFs- sequence specific.

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Creb Binding Protein

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  1. Creb Binding Protein Ahmed Sadek

  2. What is CBP? • CBP is a coactivator. • TFs: CREB and CFos • Highly related to p300. • Discovered with CREB • Integrator of STP

  3. Transcription Factors/Coactivators • Coactivators needed for transcription factors • TFs- sequence specific. Mark genes using coactivators and repressors • Coactivators function in several ways • Enzymatic activity transforms chromatin • CBP allows greater access of Proteins to DNA • Primary (enzymatic activity) and Secondary (no EA)

  4. Regulation through TFs and CAs • Trancriptional steps can be modified. • Already known: Transcription Factor concentrations. Using old techniques • Recently discovered: Coactivator concentrations. Using new techniques. • Coactivators hard to identify

  5. HATs • CBP is a histonacetyltransferase (HAT) • Acetylation (CH3 CO ) important regulator • May increase DNA binding, not always though. • Acetylation : histone tail and DNA weaken.

  6. CBP as a Disruptor • CBP disrupts coactivators and repressors. • Ex: CtBP (carboxyl terminal binding protein) • Interacts with Transcriptional corepressors. • CBP prevents this • CBP repression: wingless • Acetylating LEF-TCF-1 , cactivator B blocked

  7. CBP concentration is limited. • RR syndrome. • HIV gene expression: Interferon-a and tumor necrosis-a. • Stat-2 and NF-b • CBP contributing to transcriptional synergy • Recent evidence: promoters and TF binding sites , and CBP and multiple TFs

  8. . IFN-B enhanceosome complex. Creation of interaction surface for enhancer binding proteins. CBP: facilitator, acetylator of HMG1(Y). Derived from Rich Goodman et al

  9. Model of transcription. CBP role unclear. Enhanceosome formation, CBP- Mediator complex recruitment. Derived from Richard H Goodman Et Al.

  10. Not much known about CBP phosphorylation : CAM KINASE IV • Examples: E/cdk2- Activating genes in S. • PKA site : mediated increase of PIT-1 TF. Still mystery. • PKA and CREB • P44 MAP Kinase: 7x acetylation increase • Phosphoryltion tested • C-terminus : intramolecular conformational change must occur.

  11. CBP- P300 are very similar • Believed to be interchangeable. • Differences in development: Heterozygocity and blood problems and cancer. • Homozygous mutations are similar. • Herpesvirus protein vIRF activated by CBP but repressed by p300.

  12. Cystein/Histidine Rich dock TFs. • KIX- CREB. Contains sites for others. • Glutamine-rich C terminus- Coactivators. • No signature motifs for binding • Exception: CH3 , includes p53

  13. AT and Bromodomain • AT domain- Histone and nonhistone proteins • Not required by all TFs. • Basal transcriptional machinery contact. • Cofactors modify DNA. • Bromodomain • ATS and chromatin remodelling complexes. • Activation of Transcription and HA.

  14. KIX (blue) : simultaneous interaction • Small site: C-Myb (red) and (1 and 3 Helix bound, Important for blood development). • MLL: affinity increase. (green)

  15. Binary and ternary complex similar • *-1- *3 Helix (blue) , G1 and G2 Helix (orange)

  16. Structural Flexibility of MLL, no binding motif interaction (G2 and *3). • Change with different ligands, reducing affinity, when bound. • MLL Gene chromosomal translocation. Binding with CBP

  17. CBP and Disease CBP and Disease • RR syndrome : Retardation, deformities, hematological • Mice : 1 allele Hematoligical defect. • CBP investigation of tumor. • Interactions with repressors • E1A inhibiting activators, inhibits cell differentiation. • RR syndrome : Retardation, deformities, hematological • Mice : 1 allele Hematoligical defect. • CBP investigation of tumor. • Interactions with repressors • E1A inhibiting activators, inhibits cell differentiation.

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