1. Translational Homeostasis via eIF4E and 4E-BP1
Alan G. Hinnebusch 
Molecular Cell 
Volume 46, Issue 6, Pages (June 2012)
DOI: /j.molcel
Copyright © 2012 Elsevier Inc. Terms and Conditions

2. Figure 1
Regulation of Cap-Dependent Translation Initiation by 4E-BP1 and the Homeostatic Mechanism Coupling 4E-BP1 and eIF4E Abundance
(A) mRNA is activated by binding of eIF4F (eIF4E·eIF4G·eIF4A) to the m7G cap and PABP to the poly(A) tail, preparing it for attachment of the 43S PIC near the 5′ end. The 43S complex contains methionyl-initiator tRNAMet (blue-green shape) in a ternary complex (TC) with eIF2 bound to GTP (black ball) and other eIFs (1, 1A, 5, and 3) that stabilize 43S attachment to the eIF4F·mRNA·PABP mRNP and promote scanning. The 43S complex scans the 5′ UTR, and AUG recognition triggers hydrolysis of GTP in the TC to GDP (red ball) and Pi. Subsequent joining of the 60S subunit (catalyzed by eIF5B) and release of other eIFs forms an 80S complex competent for protein synthesis (Pestova et al., 2007).
(B) The ability of eIF4E to join with eIF4G in eIF4F is inhibited by the unphosphorylated isoform of 4E-BP1. (1) This inhibitory activity is counteracted by phosphorylation of 4E-BP1 in a manner stimulated by mTOR in nutrient-replete cells. (2) With knockdown of eIF4E, there is insufficient eIF4E to protect the unphosphorylated isoform of 4E-BP1 from ubiquitinylation by the CUL3-KLHL25 E3 ubiquitin ligase and attendant degradation by the proteasome. The inactive, phosphorylated isoform of 4E-BP1, by contrast, is stable. Elimination of unphosphorylated 4E-BP1 allows for continued eIF4F assembly and translation initiation in the face of reduced eIF4E abundance.
Molecular Cell  , DOI: ( /j.molcel )
Copyright © 2012 Elsevier Inc. Terms and Conditions