nuclear receptors

Question 1

types

Answer 1

• Type I: Steroid receptors
  • undergo nuclear translocation upon ligand activation and loose affinity for inhibition complex
  • bind as homodimers to inverted repeat DNA half sites
• Type II: RXR (retinoid X receptor) heterodimers
  • retained in the nucleus regardless of the presence of ligand
  • usually bind as heterodimers with RXR to direct repeats.
• Type III: orphan NRs
  • orphan receptors have been found by sequencing but no ligand is known

Question 2

function of active receptor

Answer 2

• The nuclear receptors bind to specific DNA sequences adjacent to the genes that the ligand regulates –> response elements in the promotor or cis-regulatory region
• often dimerize (hetero or homo)
• need cofactors

Question 3

PPARS and PPREs

Answer 3

• Some mammalian nuclear receptors are regulated by intracellular metabolites rather than by secreted signal molecules; the peroxisome proliferation-activated receptors (PPARs), for example, bind intracellular lipid metabolites and regulate the transcription of genes involved in lipid metabolism and fat cell differentiation
• PPARs are now known as a group of transcription factors that are able to induce transcription of genes that contain PPAR responsive elements (PPREs)
• Fatty acids are the natural ligands of the PPARs
• PPARalfa can upregulate lipid metabolism after heterodimerization with the retinoid x receptor (RXR)

Question 4

activation of nuclear receptor

Answer 4

• When a hydrophilic ligand binds it alters the conformation of the receptor protein, causing the bound inhibitory complex to dissociate, activating the receptor which now heads for the nucleus to find its response element in the target genes
  • While also causing the receptor to bind coactivator proteins that stimulate gene transcription

Question 5

gene repression by nuclear receptors

Answer 5

• In other cases, however, ligand binding to a nuclear receptor inhibits transcription: some thyroid hormone receptors, for example, act as transcriptional activators in the absence of their hormone and become transcriptional repressors when hormone binds
• A subset of receptors binds corepressor factors and actively represses target gene expression in the absence of ligand.
  • Corepressors are found within multicomponent complexes that contain histone deacetylase activity.
  • Deacetylation leads to chromatin computation and transcriptional repression
  • When the ligand binds to the receptor it is activated and is able to bind to the repressor relieving the gene suppression

Question 6

hydrophobic signalling molecules

Answer 6

• steroid and fatty acids and their derivatives

- Small hydrophobic ligands can directly diffuse through the plasma membrane and interact with internal receptors

Question 7

steroids

Answer 7

• Steroids are lipids that have a hydrocarbon skeleton with four fused rings; different steroids have different functional groups attached to the carbon skeleton.
• Steroid hormones include the female sex hormone, oestradiol, which is a type of oestrogen; the male sex hormone, testosterone
• They are synthesised from cholesterol
• Other hydrophobic hormones include thyroid hormones and vitamin D. In order to be soluble in blood, hydrophobic ligands must bind to carrier proteins while they are being transported through the bloodstream.
• Steroids can have a classic slow effect through binding a nuclear receptor and regulating gene expression –> the influence of the steroid on protein production takes at least 30 to 60 minutes
• Steroids can also have a fast effect via interacting with G-proteins to activate mitogen-activated protein kinases (MAPKs), adenylyl cyclase (AC), protein kinase C (PKC)

Question 8

fatty acids

Answer 8

• The lipolysis of intracellular triacylglycerols gives rise to energy-rich molecules and to regulatory molecules - among which fatty acids
• Fatty acids are important substrates for oxidation and production of cellular energy as well as precursor molecules for all lipid classes, including those that form biological membranes.
• On the other hand, free fatty acids (FFA) can become harmful to cells when present even at relatively low concentrations and thus they must be released under tight metabolic control.
• FFAs act as powerful signalling molecules, which regulate numerous cellular processes associated with lipid metabolism and which ensure precise matching of FFA release and demand.
• FFAs binds to PPARs to cause transcription
• can also act as co-activators to cause transcription of many genes

Question 9

consensus sequence

Answer 9

• The consensus sequence (or canonical sequence) is the calculated order of most frequent residues, either nucleotide or amino acid, found at each position in a sequence alignment –> mainly nice to look at the consensus sequence of responsive elements to see which genes are affected by a single nuclear receptor
• A protein binding site, represented by a consensus sequence, may be a short sequence of nucleotides which is found several times in the genome and is thought to play the same role in its different locations. For example, many transcription factors recognize particular patterns in the promoters of the genes they regulate.
• They are calculated and visualised by pattern recognition software