Nuclear/Steroid/Hormone Receptors

See also receptors

The nuclear receptor superfamily is a large superfamily whose ligands are small hydrophobic signal molecules which diffuse directly across the plasma membrane and bind to these intracellular receptor proteins. These signal molecules include steroid hormones, thyroid hormones, retinoids and vitamin D.

Nuclear receptors can be subdivided into 3 groups, depending on the source and type of their ligand.

• Classical Steroid hormone receptors. The ligands for these receptors are exclusively from endogenous endocrine sources which are regulated by negative feedback control through the hypothalamus pituitary axis. After synthesis steroid hormones are circulated in the body to their target tissues where they bind their receptors with high affinity. The receptors regulate a variety of crucial metabolic developmental events, including sexual differentiation.

• Adopted Orphan nuclear receptors whose ligands are lipids which bind with lower affinity than the classical receptors. These receptors activate a feed forward, metabolic cascade that maintains nutrient lipid homeostasis by governing the transcription of a common family of genes involved in lipid metabolism, storage, transport and elimination. Adopted orphan nuclear receptors function as heterodimers with the retinoid X receptor (RXR)

• VDR/TR/RAR/EcR-RXR Heterodimers are 4 other RXR heterodimer receptors which includes vitamine D (VDR), thyroid hormones (TR), retinoic acid (RAR) and ecdysone (EcR). The ligands for these 4 receptors and the pathways they regulate employ elements of both the endocrine and lipid sensing receptor pathways.

Nuclear receptors are all structurally related and contain the following domains:

• A/B region at the NH₂ terminal region which harbors a transcriptional activation function (AF-1).
• C region DNA binding domain is the most conserved region and contains two highly conserved zinc finger motifs that target the receptor to specific DNA sequences.
• D or hinge region that permits protein flexibility to allow for simultaneous receptor dimerization and DNA binding.
• E region which is a large COOH terminal region that encompasses the ligand binding domain, dimerization interface and ligand dependent activation function. (AF-2). The E region is the hallmark of nuclear receptors and separates NRs from other sequence specific transcriptional factors.

Mechanism of Action

Upon ligand binding, nuclear receptors undergo a conformational change that coordinately dissociates corepressors and facilitates recruitment of coactivator proteins to enable transcriptional activation. Transcriptional Cofactors for NRs include 3 main types:

• Enzyme containing co-activators are usually acetyl transferase, methyl transferase, kinase, ATPase, ubiquitin ligases or SRCs (steroid receptor co-activator) such as p160 SRC.
• Mediator complexes which contain no enzyme activity such as the TRAP complexes.
• Co-repressor complexes which are associated with histone deacetylase (HDACs).