#9 Translation Initiation

Global regualation

translation is regulated by changes in phosphorylation of initiation factors or interacting regulators

Specific regulation

translation of individual mRNAS is regulated by RNA-binding proteins/miRNAs that modulate expression of defined mRNAs

43S pre-initiation complex

40S subunit assembles with eIF2/GTP/intiator trNA, scans mRNA for AUG codon after eIF4F complex is recruited

eiF4F complex

complex of cap-binding protein + RNA-dependent ATPase +  40S subunit recuriter, attracted to the 5' cap of the mRNA

eiF5-mediated GTP hydrolyssi

upon recognition of AUG codon, GTP hydrolyiss occurs on eiF2-bound GTP, promotes dissociation of eiF components of eIF4F complex, 60S subunit joins

eIF2

Eukaryotic initiation factor 2, required for most forms of translation initiation, mediates bidning of tRNA(MET) to ribosome, alpha-subunit is phosphorylated under stress conditions

Phosphorylated eIF2

phosphorylation of Ser51 converts eiF2 from substrate to inhibitor for its exchange factor eiF2B, inhibits translation of most mRNAs but allows selective translation of mRNAs by uORFs

eIF2B

exchange factor for eIF2, swaps GDP to GTP in eiF2, 10x higher affinity for phosphorylated EiF2

Integrated stress response (IRS) pathway

stress response that uses stress-responsive eiF2a kinases to inhibit translation initiation

uORF

upstream ORFs, regulatory ORF of select mRNAs, translated under stress conditions due to perfect distance to pick up a eiF2 complex (low availability)

ATF4

uORF, enhances transcription of adaptive target genes that help the cell cope with stress

eIF4E

cap-binding subunit of eIF4F complex, facilitates 43S complex binding to mRNA translation initiation. Increased eIF4E increases transcription

Phosphorylated eIF4E

by MAPK-interacting kinases in response to hormones/growth factors, affects EiF4E affinity for cap structure/eIF4G

4E-BP1/2

translational repressors, binds eIF4E to prevent interaction, requires phosphorylation to dissociate from eIF4E

mRNA specific regulation

occurs via steric hinderance, interference with eIF4F complex assembly, interference of 60S subunit joining, miRNAs

ferritin

iron storage protein, only needed if too much iron, has an IRE in 5' URT that is bound by IRE-BP at low iron concentrations to block initiation

mRNA masking

when maternally inherited mRNAs (encode proteins crucial for embryogenesis) are translationally silent, controlled by CPE

CPE

cytoplasmic polyadenylation element, located in 3' UTR, binds CPEB, Maskin

Maskin

associates directly with eIF4E to prevent interaction with eIF4G

CPEB

prevents stable association of cytoplasmic form of CPSF with AAUAA sequence, results in short polyA tails, when phosphorylated will cause Maskin to dissociate

CPSF

cleavage and polyadenylation specificity factor, binds AAUAA to recruit polyA polymerase to extend polyA tail

PAB

polyA binding protein, allows association of 5'/3' ends of mRNA with eIF4G/eIF4E to recruit 40S subunit