Cap-dependent translation initiation in eukaryotes is regulated by a molecular mimic of elF4G

elF4G uses a conserved Tyr-X-X-X-X-Leu-phi segment (where X is variable and phi is hydrophobic) to recognize elF4E during cap-dependent translation initiation in eukaryotes. High-resolution X-ray crystallography and complementary biophysical methods have revealed that this elF4E recognition motif undergoes a disorder-to-order transition, adopting an L-shaped, extended chain/alpha-helical conformation when it interacts with a phylogenetically invariant portion of the convex surface of elF4E. Inhibitors of translation initiation known as elF4E-binding proteins (4E-BPs) contain similar elF4E recognition motifs. These molecules are molecular mimics of elF4G, which act by occupying the same binding site on the convex dorsum of elF4E and blocking assembly of the translation machinery. The implications of our results for translation initiation are discussed in detail, and a molecular mechanism for relief of translation inhibition following phosphorylation of the 4E-BPs is proposed.