Receptors for Steroid Hormones and Thyroid Hormones Contain Similar DNA-Binding Domains and Different Hormone-Binding Domains

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Receptors for steroid hormones and thyroid hormones contain similar DNA-binding domains and different hormone-binding domains. Struttura di due domini presenti nei recettori nucleari. I Recettori nucleari contengono due comini conservati: (1) un dominio di legame al DNA in una zona centrale della sequenza proteica e (2) un dominio di legame al ligando in prossimità del terminale carbossilico. Un modello per l’azione del recettore per gli estrogeni (ER). Abbr: E, estrogen; R, receptor; ERE, estrogen response element; GF, growth factor; TBP, TATA binding protein; TAFs, TBP-associated factors; pol II, RNA polymerase II. Riconoscimento specifico di sequenze da parte dei recettori per gli steroidi. Sono mostrate le sequenze degli aminoacidi nel dominio di legame al DNA del recettore per glucocorticoidi. Gli aminoacidi nel P-box e D-box sono importanti, rispettivamente, per il riconoscimento e la dimerizzazione con il DNA Stabilizzazione da parte del recettore per gli steroidi del complesso di pre-inizio della trascrizione Sequenze consenso dei siti di DNA, chiamate elementi di risposta, che si legano al recettore per i glucocorticoidi (GRE), al recettore per gli estrogeni (ERE), al recettore per la vitamina D 3 (VDRE), al recettore per l’ormone tiroideo (TRE) e al recettore per l’acido retinoico (RARE). Le ripetizioni invertite in GRE e ERE e le ripetizioni dirette in VDRE, TRE e RARE sono indicate con le frecce. Ligand-dependent recruitment of multiple coactivator complexes. Upon ligand binding, the receptors recruit different coactivator complexes. The complex CBP/p160/PCAF possesses histone acetyltransferase activity, the SWI/SNF complex possesses ATP-dependent chromatin remodeling activity, and the TRAP/DRIP complex may recruit the RNA polymerase II (RNAP II) holoenzyme. Recruitment of the complexes may be sequential or combinatoria. It is conceivable that chromatin remodeling complexes are initially recruited to the promoter. These factors may relieve the repression imposed by high- order chromatin structure and allow a second acetylation-dependent step on gene activation. Activation would require the combinatorial of subsequent action of additional complexes that include the TRAP/DRIP complex.

Hypotetical minimal model of a non-DNA binding form of a steroid receptor. This form of the receptor cannot bind to DNA because the DNA binding site is blocked by the 94 kDa hsp protein or by some other constituent. Molecular weight of this complex is approximately 300 kDa. Ligand binding to nuclear hormone receptor. The ligand lies completely surrounded within a pocket in the ligand binding domain. The last alpha helix, folds into a groove on the side of the structure on ligand binding

Coactivator recruitment. The binding of a nuclear hormone receptor induces a conformational change in the ligand-binding domain. This change in conformation generates favorable sites for the binding of a coactivator Estrogen receptor-tamoxifen complex. Tamoxifen binds in the pocket normally occupied by estrogen. However, part of the tamoxifen structure extends from this pocket, and so helix 12 cannot pack in its usual position. Instead, this helix blocks the coactivator-binding site. Enzymes that catalize such reactions are called Histone acetyltransferases (HATs)

Structure of the Histone acetyltranserase. The ammino-terminal tail of the histone H3 extends into a pocket in whicha lysine side chain can accept an acetyl group from acetyl CoA bound in a adjacent side.

Chen R A , Goodman W G Am J Physiol Renal Physiol 2004;286:F1005-F1011

SH SH SH SH

DAG DAG PIP PLC PKC 3

α γ Ras-GTP c-Raf Src Shc P P PKC IP GTP P 3 β Pi Pi

c-Raf AKT P AC Shc Grb2 SH PKA P cAMP Sos PI3-4-5 P p85 PI3-Kinase S rc p110 Signal transduction systems Rapid response outcomes PKA Ion channels Scaffold PKC Transcription PLC Translation SH PI3K Protein kinase/phosphatase SH Ras/MAPK Structural protein SH Steroid hormone E-NOS Signalling enzymes EGFR/matrix metalloproteinase Feddback regulation

Schematic diagram of a steroid hormone interacting with four classes of membrane receptors to generate second messengers linking to variety of signal-transduction systems. A) Three classes of membrane receptor are shown illustrating the classic nuclear steroid-hormone receptor associated with a caveola. Aa) The receptor is technically outside the cell and is associated with the outer surface of the plasma membrane in the flask of the caveola. Ab) The receptor is tethered by a scaffolding protein to the plasma membrane on the inner surface of the caveola. Ac) The receptor is tethered to the caveolae by a palmitic acid molecule that is esterified to a recoptor Ser or Thr with the fatty-acid side chain “inserted” into the membrane (palmitoylation). B) A G-protein coupled receptor with its ligand binding domain on the outside of the cell and a seven-membrane spanning peptide transition followed by an intracellular peptide domain that can bind G alpha beta and gamma proteins. C) A single-spanning membrane receptor with intrinsic kinase activity that might be functional as a monomer. D) Same as C except a homodimer. Caveolae are flask-shaped membrane invaginations present in the outer cell membrane of many cells; they are believed to serve as a platform to accumulate or dock signal transduction-related molecules. The signal transduction systems are listed as candidates for madiating rapid responses to steroid and are based to published data. The details remain to be defined on the basis of careful experimentation. The two ovals with Ras-GTP and c-Raf are to suggest that c-Raf was recruited to the complex. AC adenylyl cyclase; DAG, diacylglycerol; EGFR, epidermal groth factor receptor; e-NOS, endothelial nitric oxide synthase; IP3, inositol triphosphate; MAP, mitogen-activated protein; PI3K, phosphatidylinositol 3-kinase; PIP3, phosphatidylinositol triphosphate; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholiphase C Extracellular

Intracellular

Endoplasmic reticulum

Diagram illustrating the manner in which Ca 2+ acts as an extracellular messenger. Activation of the Ca2+-sensing receptor (by 2+ binding of Ca to negatively charged regions) activates phospholipase C (PLC; possibly via Gq protein), leading to increased 2+ intracellular levels of diacyglycerol (DG) and inositol 1,4,5-trisphosphate (IP 3), and concomitant release of Ca from internal 2+ 2+ stores (e.g. the endoplasmic reticulum). The rise in Ca i is sustained by influx of Ca through channels in the plasma 2+ membrane. The Ca -sensing receptor can also reduce receptor-mediated increases in cAMP levels (possibly via G i protein). The Ca 2+ -induced changes in the activities of these second messenger systems leads to changes in the activities of a series of kinases (e.g. PKC and PKA), which in turn alter the biological activities of the cell. AC, adenylate cyclase; PIP 2, phosphatidylinositol bisphosphate.