Cap-free structure of eIF4E suggests a basis for conformational regulation by its ligands.
The activity of the eukaryotic translation initiation factor eIF4E is modulated through conformational response to its ligands. For example, eIF4G and eIF4E-binding proteins (4E-BPs) modulate cap affinity, and thus physiological activity of eIF4E, by binding a site distal to the 7-methylguanosine cap-binding site. Further, cap binding substantially modulates eIF4E's affinity for eIF4G and the 4E-BPs. To date, only cap-bound eIF4E structures were reported. In the absence of structural information on the apo form, the molecular underpinnings of this conformational response mechanism cannot be established. We report here the first cap-free eIF4E structure. Apo-eIF4E exhibits structural differences in the cap-binding site and dorsal surface relative to cap-eIF4E. Analysis of structure and dynamics of apo-eIF4E, and changes observed upon ligand binding, reveal a molecular basis for eIF4E's conformational response to these ligands. In particular, alterations in the S4-H4 loop, distal to either the cap or eIF4G binding sites, appear key to modulating these effects. Mutation in this loop mimics these effects. Overall, our studies have important implications for the regulation of eIF4E.
Volpon
Laurent
L
Department of Pathology and Cell Biology, Institute for Research in Immunology and Cancer, Université de Montréal, Pavillion Marcelle-Coutu, Chemin Polytechnique, Montréal, QC, Canada.
Osborne
Michael J
MJ
Topisirovic
Ivan
I
Siddiqui
Nadeem
N
Borden
Katherine L B
KL
D001665:Binding Sites / Q000235:genetics; D039561:Eukaryotic Initiation Factor-4E / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D017433:Protein Structure, Secondary / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics
D039561:Eukaryotic Initiation Factor-4E; D008024:Ligands