Cap-dependent translation initiation in eukaryotes is regulated by a molecular mimic of eIF4G.
eIF4G uses a conserved Tyr-X-X-X-X-Leu-phi segment (where X is variable and phi is hydrophobic) to recognize eIF4E during cap-dependent translation initiation in eukaryotes. High-resolution X-ray crystallography and complementary biophysical methods have revealed that this eIF4E 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 eIF4E. Inhibitors of translation initiation known as eIF4E-binding proteins (4E-BPs) contain similar eIF4E recognition motifs. These molecules are molecular mimics of eIF4G, which act by occupying the same binding site on the convex dorsum of eIF4E 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.
Laboratories of Molecular Biophysics, Rockefeller University, New York, New York 10021, USA.
J
J
Marcotrigiano
A C
AC
Gingras
N
N
Sonenberg
S K
SK
Burley
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D017124:Conserved Sequence / Q000235:genetics / Q000502:physiology; D003460:Crystallization; D018360:Crystallography, X-Ray; D039561:Eukaryotic Initiation Factor-4E; D039562:Eukaryotic Initiation Factor-4F; D039603:Eukaryotic Initiation Factor-4G; D039642:Eukaryotic Initiation Factors; D006153:Guanosine Diphosphate / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D010448:Peptide Initiation Factors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000235:genetics*; D017433:Protein Structure, Secondary; D012315:RNA Caps / Q000235:genetics*; D017384:Sequence Deletion
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C491300:EIF4G2 protein, human; C499527:Eif4ebp1 protein, mouse; C104828:Eif4g2 protein, mouse; D039561:Eukaryotic Initiation Factor-4E; D039562:Eukaryotic Initiation Factor-4F; D039603:Eukaryotic Initiation Factor-4G; D039642:Eukaryotic Initiation Factors; D010446:Peptide Fragments; D010448:Peptide Initiation Factors; D010750:Phosphoproteins; D012315:RNA Caps; C111106:7-methylguanosine 5'-diphosphate; D006153:Guanosine Diphosphate