Translational Control of Synaptic Plasticity and Memory - Biophysical Approaches to Translational Control of Gene Expression - page 286

Fig. 14.1 Regulation of translation initiation by eIF4F complex formation The eukaryotic mRNA
5¢-cap structure facilitates ribosome recruitment to the mRNA by the eIF4F complex, which con-
sists of three subunits: (1) eIF4E, the cap binding protein; (2) eIF4A, an RNA helicase that unwinds
the secondary structure of the mRNA 5¢ UTR; and (3) eIF4G, a large scaffolding protein that
bridges the mRNA to the 43S preinitiation ribosomal complex. Once bound to the 5¢ end of the
mRNA, the 43S ribosomal complex traverses the 5¢ UTR in a 5¢ -3 ¢ direction, until it encounters
the initiation codon (AUG) where translation begins. 4E-BP inhibits cap-dependent translation
initiation by preventing the assembly of the eIF4F complex. 4E-BP and eIF4G compete for binding
to the convex dorsal surface of eIF4E. Phosphorylation of 4E-BP by mTOR reduces its affinity for
eIF4E and thus leads to eIF4F complex formation and translation initiation

secondary structure of the 5¢ UTR of the mRNA, (2) eIF4E, that specifically interacts
with the cap structure (Sonenberg et al. 1979 ), and (3) eIF4G, a large scaffolding
protein (of which there are two gene products, eIF4GI and eIF4GII) that binds to
both eIF4E and eIF4A and bridges the mRNA to the 43S preinitiation complex.
Thus, eIF4G serves as a modular scaffolding protein to assemble the protein machin-
ery that directs the ribosome to the mRNA (Fig. 14.1 ). Because eIF4E generally
exhibits the lowest expression level of all the eukaryotic initiation factors, the cap-
recognition step is rate-limiting for translation and a major target for regulation.
A second major translational control mechanism is mediated by the translation
initiation factor eIF2 (which is composed of three subunits a , b , and g ) (Sonenberg
and Hinnebusch 2009 ) . eIF2 binds Met-tRNA i Met and GTP to form a ternary com-
plex eIF2 Met-tRNA i Met . The ternary complex binds the small 40S ribosomal

subunit, which is associated with other eIFs to form a 43S ribosomal preinitiation
complex. Upon 60S subunit joining, GTP is hydrolyzed by eIF5 leading to the
release of eIF2

⋅ GTP ⋅

GDP from the ribosome. An exchange of GDP for GTP on eIF2 is
catalyzed by eIF2B and is required to prepare the functional ternary complex for a
new round of translational initiation. Phosphorylation of Ser51 in the a subunit of

⋅