BIOCHEMICAL ASPECTS (B) Mechanism of Action of Steroid Hormones• STEROID HORMONE RECEPTORS – Expression , Distribution, Regulation, Interaction with DNA (post- translational & post - transcriptional)
SYNOPSIS• Steroid hormones- A brief introduction• Steroid hormone receptor Types & structure• Mechanism of hormone action• Role in gene expression Expression Distribution Regulation Interaction with DNA• Refrences• Conclusion
Steroid hormones• The steroid hormones are synthesized by endocrine glands such as the gonads (testis and ovary), the adrenals and (during gestation) by the fetoplacental unit, and are then released into the blood circulation.• Steroid hormones are lipophilic molecules having low-molecular weight hence it enters the by simple diffusion.• The parent compound from which all steroid hormones are derived is cholesterol.• They all contain the same cyclopentanophenanthrene ring and atomic numbering system as cholesterol.
STEROID HORMONE AND GENE EXPRESSION• SH can have an activating or inhibiting effect on the genes.• Not all genes are regulated by SH but a particular set of genes.• These genes contain specific DNA sequences that are located in multiple copies in the promoter region and are called as Hormone Response Elements (HREs).• The unique action of each type of steroid results from the different receptor proteins and HREs involved.• In different types of cells, the same steroid hormone may activate different set of genes.• The genetic programs that they establish or modify affect virtually all aspects of the life, covering such diverse aspects as embryogenesis, homeostasis, reproduction, cell growth, or death.
STRUCTURE• As all the steroid hormones are derived from cholesterol their basic structure is similar.• They contain three hexagonal carbon rings and a pentagonal carbon ring to which a side-chain is attached. PROGESTERONE ALDESTERONE CORTISOL
FUNCTIONS• They act both on peripheral target tissues and the central nervous system (CNS).• GONADAL STEROIDS influence the sexual differentiation of the genitalia and of the brain, determine secondary sexual characteristics during development and sexual maturation, contribute to the maintenance of their functional state in adulthood and control or modulate sexual behaviour.• ADRENAL STEROIDS modulate metabolism of carbohydrates, act as immunosuppressive and anti inflammatory components, control excretion of electrolytes, etc.CLASSIFICATION• Steroid hormones can be grouped into five groups by the receptors to which they bind: Glucocorticoids Mineralocorticoids Androgens Estrogens Progestagens
STEROID HORMONE RECEPTOR• Steroid hormone receptors are proteins that have a binding site for a particular steroid molecule.• Steroid hormone receptors are found in the cytosol and also in the nucleus of target cells.• Steroid hormone receptor belong to NUCLEAR RECEPTOR FAMILY.• They are ligand-activated proteins that regulate transcription of selected genes.• Their response elements are DNA sequences that are bound by the Hormone- Receptor complex.
MOLECULAR STRUCTURE OF SHR• The molecular structure of SHR shows presence of five distinct regions :• Two end terminals – N terminal & C terminal.• A hinge region• Two domains – DNA binding domain & Ligand binding domain. DNA Ligand binding binding domain domain N terminal C terminal Hinge region DIAGRRAMATIC REPRESENTATION OF SRUCTURE OF SHR
N TERMINAL• It is also called as VARIABLE terminal as the length of this terminal is variable for every hormone.• Its length ranges between 100 to 500 amino acids.• It contains several autonomous transactivation domain.DNA BINDING DOMAIN• About 59-76% of amino acid sequences are similar in all SHRs.• It consists of zinc fingers and forms a highly conserved residue core.• Usually present in the centre of receptor molecule.• This is the region that interacts with the HRE.HINGE REGION• It is a poorly conserved region, serves as a connection between the DBD and LBD.• It allows the DBD and LBD to adopt different conformations without creating a steric hindrance.• Domain also harbors a nuclear localization signal.
LIGAND BINDING DOMAIN• Largest domain of SHR and forms 30% part of the receptor• It is moderately conserved.• It consists of about 290 amino acids.• This domain with the heat shock proteins (chaperone proteins) in cytoplasm.C Terminal• the C-terminal is present at the end of LBD.• It is a highly variable terminal with amino acids ranging from 530 to 984.• The terminal connects the molecule to its pair in the homodimer or heterodimer. It may affect the magnitude of the response.
SEQUENCE OF ACTION OF STERIOD HORMONE Steroid Hormone enter cell & bind to receptorTranslocation of activated receptor- ligand complex into nucleus Binds to another specific receptor on the chromatin. Steroid receptors form dimers Act on DNA Augmentation or Suppression of transcription
EXPRESSION• When the steroid hormone passes through the cell membrane it enters cytoplasm and binds to steroid hormone receptor.• Both the components undergo conformational and structural changes to become activated.• The activation step is critical as it prepares the complex to bind to DNA sequence.
DISTRIBUTION• Once the hormone receptor complex gets activated it enters the nucleus.• Activated receptors bind to "hormone response elements", which are short specific sequences of DNA which are located in promoters of hormone-responsive genes. In most cases, hormone-receptor complexes bind DNA in pairs, as shown in the figure below.
REGULATION• Activated receptors bind to "hormone response elements", which are short specific sequences of DNA which are located in promoters of hormone-responsive genes. In most cases, hormone-receptor complexes bind DNA in pairs, as shown in the figure below.• Transcription from those genes to which the receptor is bound is affected. Most commonly, receptor binding stimulates transcription. The hormone-receptor complex thus functions as a transcription factor.
• Within the nucleus along with the DNA, the hormone-receptor complex also interacts with the transcription machinery, regulatory proteins, etc.• There two models about how the hormone interacts with the DNA.Ist Model• The DNA is wrapped tightly in nucleosome which is composed of histone fold domains.• The nucleosome also consists an amino terminal tail rich in lysine .• Acetylation of tail lysines reduces the affinity of histone to DNA, thus making it accessible to transcription factors.• The architecture of the nucleosome is also maintained.IInd Model• According to the 2nd model NURF induces an ATP dependent remodeling of chromatin resulting in an unstable or transient opening of promoter nucleosome.• In this case,NF1 acts as a wedge to stabilize the open conformation of chromatin.
REGULATION• The action of steroid hormones is regulated by the presence of two components- Coactivators and Corepressors.• The activation or inhibition f transcription of genes by SH depend on the presence of these components.• They are a class of protein whose mechanism & function is synonymous to that of coenzymes & inhibittors in case of enzyme action . Corepressors• Not much known about them.• Antagonizes the effect of hormone to stimulate transcription from reporter genes.
COACTIVATORS• Made up of amino acid motif.• It is distinguished into two classes ;i. Interacts with sequence specific transcription factors.ii. Interacts with general machinery on core promoter elements. Eg. TATA box binding protein.
REFERENCES• BOOKSEndocrinology by HadleyClinical endocrinologyGeneral endocrinology by Bagrara & Tumer