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DNA binding domains and activation domains of transcription factors

DNA binding domains and activation domains of transcription factors. A survey of DNA binding domains. Zn -containing domains 6 Cys and 2 Zn: Gal4 Zn fingers Many eukaryotic transcription factors Basic-leucine zipper proteins (hetero)Dimers, eukaryotic activators Helix-turn-helix

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DNA binding domains and activation domains of transcription factors

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  1. DNA binding domains and activation domains of transcription factors

  2. A survey of DNA binding domains • Zn -containing domains • 6 Cys and 2 Zn: Gal4 • Zn fingers • Many eukaryotic transcription factors • Basic-leucine zipper proteins • (hetero)Dimers, eukaryotic activators • Helix-turn-helix • Many bacterial regulators, e.g. l repressor • Homeodomain proteins involved in segment determination in eukaryotes • Basic-helix-loop-helix proteins • (hetero)Dimers, differentiation factors

  3. Zinc fingers • Cys or His amino acids donate electron pairs to a tetrahedral configuration organized by a Zn++ ion • Several different types TFIIIA • C2H2 (e.g. TFIIIA) • C2C2 (e.g. Glucocorticoid receptor) • C6 (e.g. GAL4) • GATA • Different functions • DNA binding • Protein-protein interactions • Each finger contacts 3 consecutive bp in major groove

  4. C2H2 Zn finger

  5. C2-C2 Zn Finger • Found in steroid receptors • Glucocorticoid receptor • Three functions in central domain • DNA binding (Zn finger) • Dimerization (Zn finger) • Activation domain • C terminus binds steroid hormone • N terminus activates transcription N C 403 491 777

  6. Basic-leucine zipper proteins View down long axis of DNA Lateral view of DNA S. Harrison lab: cFos-cJun heterodimer, DBD, 2 complexes Nature 1995 Jan 19;373(6511):257-61 Images via NCBI and their Cn3D program.

  7. Helix-turn-helix (HTH)

  8. Helix-loop-helix proteins Ma PC, Rould MA, Weintraub H, Pabo CO: MyoD bHLH domain-DNA complex Cell 1994 May 6;77(3):451-9

  9. Transcriptional activator domains (ADs)

  10. 3 general types of activator domains • Acidic • Amphipathic helix, acidic amino acids on one face • No consistent secondary or tertiary structure has been identified • Glutamine-rich (Q-rich) • Pro-rich (P-rich)

  11. No correspondence between type of DBD and type of AD • Examples of proteins with acidic AD • GAL4 (Zn2Cys6) • AP1 (bZIP) • VP16 (no DBD) • l repressor (HTH) • Examples of proteins with Q-rich AD • Sp1 (Zn finger) • Antp (homeodomain) • Oct (POU-homeo)

  12. Lack of fixed structure in activator domains • DBDs of transcription factors form discrete structures that can be analyzed by X-ray crystallography and NMR • The ADs do not generate identifiable electron density in the crystallographic analysis. • This indicates that they do not form discrete structures. • One hypothesis is that the ADs are unstructured until they interact with their targets. • This is an induced fit model.

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