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Signal transduction

Signal transduction. Intracellular (nuclear) receptors webversion. Dimension of time and solubility. 3’. 5’. Role of intracellular receptors in signal transduction. protein. steroid-thyroid-retinoid- receptor superfamily. Nuclear hormone receptor superfamily.

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Signal transduction

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  1. Signal transduction Intracellular (nuclear) receptors webversion

  2. Dimension of time and solubility

  3. 3’ 5’ Role of intracellular receptors in signal transduction protein

  4. steroid-thyroid-retinoid- receptor superfamily Nuclear hormone receptor superfamily

  5. Steroid-thyroid-retinoid- receptor superfamily • Development • Differentiation • Cell-cell interactions • Nutrient sensing

  6. Some ligands of the steroid-thyroid-retinoid receptor superfamily

  7. Module 1: Figure aldosterone and cortisol biosynthesis „prereceptorial” activation of hormones - biotransformation Cell Signalling Biology www.cellsignallingbiology.org 2007

  8. Steroid-thyroid-retinoid- receptor superfamily ~ 150 protein (caterpillar – human) similar structure – regulation of transcription ligands: hormones vitamins drugs, fatty acids lipid soluble DNA ligand other transcription factors binding to regulation ligand dependent non receptor factors

  9. Principal mechanism of action of steroid hormones

  10. AF1 LBD - AF2 DBD Helix 12 A/B C D E/F Nuclear Hormone Receptor Superfamily Type II family Type I family Steroid family Non-steroid family GR TR a, b PR RAR a, b, g AR RXR a, b, g VDR MR PPAR a, g, d ER a, b CAR, SXR/PXR LXR a, b, FXR

  11. AF1 LBD - AF2 DBD Helix 12 A/B C D E/F Nuclear Hormone Receptor Superfamily Type II family Type I family Steroid family Non-steroid family GR TR a, b PR RAR a, b, g AR RXR a, b, g VDR MR PPAR a, g, d ER a, b ER GR GR CAR, SXR/PXR HRE LXR a, b, FXR homodimer

  12. AF1 LBD - AF2 DBD Helix 12 A/B C D E/F Nuclear Hormone Receptor Superfamily Type II family Type I family Steroid family Non-steroid family GR TR a, b PR RAR a, b, g AR RXR a, b, g VDR MR PPAR a, g, d ER a, b RXR TR CAR, SXR/PXR HRE LXR a, b, FXR heterodimer

  13. Orphan receptors unknown LIGAND sequence homology unknown FUNCTION retinoids terpenoids farnesol long chain fatty acids PGJ2 analogues more than 40 orphan subfamilies ligand „candidates” small lipofilic

  14. Steroid receptors GR glucocorticoid MR mineralocorticoid GR GR PR progesteron AR androgenic ER estrogen RXR heterodimers TRthyroid hormone RXR RAR RARtrans RA VDR 1,25 – (OH)2 – VD3 PPAReicosanoids (peroxisome proliferator activated receptor) EcR ecdyson RXR9 cisz RA, terpenoids

  15. Consensus sequences of DNA response elements for different nuclear hormone receptors The glucocorticoid receptor and oestrogen receptor bind to their respective response elements as homodimers. The response element is an inverted repeat The vitamin D receptor, the thyroid hormone receptor and the retinoic acid receptor bind to their respective response elements as heterodimers (with RXR). The response element is an direct repeat. The spacing between these repeats determines the specificity of the interaction. Fig 11.42 Lodish et al. Molecular Cell Biology

  16. Similar structure, different length

  17. Conserved domains of transcription factors in nuclear-hormone receptor superfamily A/B C E AF-2 domain Two non-repeating C4 Zn finger motif AF-1 domain Fig 11.41 Lodish et al. Molecular Cell Biology

  18. Structure of nuclear receptors 2. coactivators transactivators proteins of transcription DBD conservative DNA binding dimerisation binding to HRE two Zn fingers ( helix dimerisation) A/B variable connections with

  19. DBD structures

  20. NH2 HOOC Y N K K H C C C V G H H Zn Zn R L Q H C C C H H R E Zn S R L A S S F K V E Zinc Finger C H Zn C H Finger type Transcription Factors Gal4 C6 Steroid hormone C4 + C6 C2H2 C4 C5 C6

  21. Structure of nuclear receptors 2. coactivators transactivators proteins of transcription DBD conservative DNS binding dimerisation binding to HRE two Zn fingers LBD ligand binding with high affinity (KM> 1 nM) selective, stereospecific, reversible ( helix dimerisation) hsp C terminal part transactivator protein binding dimerisation D possible change of conformation hinge function „folds” translocation translocation A/B variable connections with

  22. Steroid type Hsp90 - GR

  23. Steroid or hsp90

  24. Steroid or hsp90

  25. Grouping according to the localisation of the receptor (1) A. steroid type GR, AR, PR, MR, ER no silencer effect but repressor effects longer A/B domain associated to hsp when no ligand is bound no HRE binding without ligand must dimerise for HRE binding activation domains agonist, antagonist binding sites (different) importance of LBD

  26. Grouping according to the localisation of the receptor (2) short A/B domen no hsp association binds to HRE without ligand can bind as a monomer B. Thyroid type TR, RAR, VDR, RXR, PPAR, orphan silencer effect

  27. thyroid type

  28. Modulating factors 1. presence of ligands 2. activation without ligands 3. receptor phosphorylation 4. structure of binding site – chromatin structure 5. nuclear non-receptor transcription factors

  29. Modulating factors presence of ligands ligand metabolism (e.g. metamorphosis, prostate: dihydrotestosterone production enhanced AR effect) activation without ligands effect of neurotransmitters on sexual behaviour effect of growth factors membrane receptor nuclear receptor dopamine PR, ER, VDR activating effect EGF activates ER – it can be prevented by antiestrogens „crosstalk”

  30. Modulating factors receptor phosphorylation needed for transactivation? roles needed for receptor transport? activation without ligands? nuclear DNA-dependent protein kinases „half binding site” the order of heterodimer according to the binding site hormone-induced changes in DNA conformation multiple sites presumably (also) after DNA binding size of the „interface” structure of binding site – structure of chromatin RXR - TR TR - VDR alteration of nucleosome structure

  31. Chromatin-based mechanisms Histone deacetylases (HDAC) corepressors since they don’t recognize DNA directly but are recruited by association with sequence-specific, DNA-binding proteins. HDAC cleaves the acetyl moiety from histone tails. Thyroid hormone receptor (TR) provides an example of a DNA binding protein that switches activity by changing its associated cofactor.In the absence of thyroxin, TR associates with a target gene but inhibits transcription because TR recruits an HDAC complex.Thyroxin induces a conformational change upon binding TR and causes dissociation of the HDAC and association of a HAT complex. This contributes to transcriptional activation.

  32. General Scheme for Activation of Gene Transcription by Nuclear Hormone Receptors Robyr, Wolffe, Wahli Mol. Endocrinol 2000

  33. Therapeutic implications

  34. Nuclear receptor mutations(LBD, DBD) familiar diseases X-linked AR mutation testicular feminisation no androgen response glucocorticoid resistance hypercortisolism without Cushing symptomes vitamin-D-resistent rachitis TR mutations in LBD rare syndromes ? Receptor deficiency

  35. Therapeutic significance of receptor detection mamma carcinoma ER antiestrogen therapy leukemias lymphoid tumors uterus tumors GR antisteroids: no dissociation competition inhibition of dimerisation tamoxifen antiestrogen ER ligand research: osteoporosis, mamma carcinoma, menopausa VDR ligand research: osteoporosis, prostate carcinoma,

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