MARIA - LECTURE 6 Flashcards
what regulates initiation of translation
of the eIF4F complex, eIF4E is the least abundant
mRNAs compete for access
how does structure of cap affect competition for eIF4F
how is eIF4F assembly controlled by mTOR
what does the mTOR pathway regulate
regulates cell size and growth
rapamycin increases lifespan
mTOR signaling pathway is the most frequently deregulated pathway in cancer cells
what kind of mRNAs are translated when eIF4F is limiting/is increased
eIF4F and cancer
associated with poorer outcome/lower survival
what does eIF2 bind
forms the ternary complex with the itRNA-met and GTP
how does the eIF2 cycle work
eIF2 has three subunits, alpha subunit is phosphorylated on serine 51 by eIF2alpha kinases
eIF2 hydrolyzes GTP into GDP during translation initiation
eIF2B is in charge of bringing a new GTP to make eIF2 active again so the cycle can restart
eIF2alpha kinases sequester the complex
what are the different eIF2alpha kinases and what are their effects
by sequestering eIF2, general translation decreases and gene specific translation increases, at the same time
how does HRI (heme regulated inhibitor) work
low hemoglobin, HRI is active, blocks eIF2, low translation for globins
high hemoglobin, HRI is inactive, does not block translation
how does PKR (protein kinase R) work
what are some countermeasures that viruses have developed against PKR
how does PERK work
how does GCN2 (general control non-repressed 2) work
what is the general mechanism of GCN4 and general amino acid control (GAAC)
how is GCN4 expression controlled in non starvation conditions
High ternary complex levels (eIF2-GTP-tRNAiMet)
The ribosome scans from the 5’cap and initiates translation at uORF1
Translation terminates at the uORF1 stop codon but the 40S ribosomal subunit remains attached to it
The 40S ribosome continues scanning and recruits a new ternary complex 🡪 enables the ribosome to translate uORF4, which contain a strong ribosome release signal, causing the completely disassemble of ribosome
As a result, GCN4 protein is not produced because the ribosomes cannot reach it.
how is GCN4 expression controlled in AA starvation conditions
Low Ternary complex level
Ribosomes still initiate translation at uORF1
At uORF4, reduced ternary complex availability means that not all ribosomes recruit a new ternary complex.
Some 40S ribosomal subunits continue scanning and reach the GCN4 start codon, allowing translation of GCN4.
how does ATF4 regulation happen in stress vs non stress conditions
what is the structure of eIF2B
vanishing white matter disease and eIF2B
what does ISRIB do
ISRIB stimulates translation even through eIF2alpha is phosphorylated
how does ISRIB rescue memory during traumatic brain injury
how do we figure out how long it takes for a ribosome to translate an ORF
