Nutrient Sensing and mTOR Signalling Flashcards
In what circumstances is control of mRNA translation important?
In cell growth and proliferation = speeds up protein synthesis to grow faster
Respond to hormones, growth factors and nutrients
Controls synthesis of specific proteins during development
Respond to stresses or energy depletion
What happens to protein synthesis under low intracellular amino acid levels?
Protein synthesis is inhibited
Why is protein synthesis inhibited under low intracellular amino acid levels?
Because protein synthesis is an energy demanding process and requires amino acids
What is needed for full translation in eukaryotes?
5’ CAP = 7-methyl GTP
Poly A tail = role in mRNA splicing, transport, stability and translation
What impairs translation when amino acid levels are low?
4E-BP1 binds euk initiation factor 4E and prevents its interaction with the eIF4G protein.
This interaction blocks the formation of the eIF4F complex, which is crucial for the initiation of translation in eukaryotic cells
What occurs to 4E-BP1 when amino acids are present?
4E-BP1 is phosphorylated by the mTOR pathway
This leads to euk initiation factor 4G binding eIF4E
What does eIF4g function as?
Scaffold proteins that recruits other eIFs and the ribosome to the cap-moiety
What is eIF4A function?
RNA helicase
Unwinds secondary structure in the 5’UTR = allowing ribosome to efficiently scan AUG start codon
What is the TRANSLATION initiation complex?
Together eIF4E, 4G, and 4A = eIF4F translation initiation complex
How does nutrient withdrawal affect translation?
Inhibits eIF4E-dependent translation because 4E-BP1 blocks it
What is the role of mTOR?
Nutrient sensing
When amino acids are present mTOR phosphorylates 4E-BP1 inhibiting it from blocking eIF4E = allowing protein translation to occur
mTOR phosphorylates S6K1 to activate it = results in pS6 being phosphorylated and activated
Leading to cell growth/prolifation and translational control
What are mTOR downstream signalling targets?
4E-BP1 and S6K1
How does 4E-BP1 repress cap-depdenent translation?
Through impairing eIF4G ability to recruit other euk initiation factors to mRNA
Where was Rapamycin disovered and what properties were discovered?
Discovered in soil sample
Used as anti-fungal agen
Discovered Rapamycin has immunosuppressive effects (used as anti-rejection drug for transplants) AND anti-tumour effects
What protein does Rapamycine bind to?
FKBP12
What type of kinase is mTOR?
Serine/Threonine Kinase
What is mTOR master regulator of and how does it perform regulation?
Translational machinery via phoshporylation
What effect does Rapamycin/FKBP12 have on mTOR?
Inhibits mTORC1
What are the components of mTORC1?
PRAS40 and Raptor
Deptor and mLST8
What are the components of mTORC2?
Protor, mSIN1 and Rictor
Deptor and mLST8
What components do mTORC1 and mTORC2 have in common?
Deptor and mLST8
What domains does mTOR have?
HEAT repeats
FAT = focal adhesion targeting domain
FATC
FRB = where Rapa/FKBP12 binds???
Kinase domain
What in the heart does mTOR regulate?
Angiogenesis through VEGF expression
(vascular endothelial growth factor)
What occurs in tuberous sclerosis complex (TSC)?
Autosomal dominant disorder
Characterized by haratomas = benign tumours in many organs
Growths within the brain = calcify with age and become hard or sclerotic (scarred)
