title: The Structures of eIF4E-eIF4G Complexes Reveal an Extended Interface to Regulate Translation Initiation.
abstract: Eukaryotic initiation factor 4G (eIF4G) plays a central role in translation initiation through its interactions with the cap-binding protein eIF4E. This interaction is a major drug target for repressing translation and is naturally regulated by 4E-binding proteins (4E-BPs). 4E-BPs and eIF4G compete for binding to the eIF4E dorsal surface via a shared canonical 4E-binding motif, but also contain auxiliary eIF4E-binding sequences, which were assumed to contact non-overlapping eIF4E surfaces. However, it is unknown how metazoan eIF4G auxiliary sequences bind eIF4E. Here, we describe crystal structures of human and Drosophila melanogaster eIF4E-eIF4G complexes, which unexpectedly reveal that the eIF4G auxiliary sequences bind to the lateral surface of eIF4E, using a similar mode to that of 4E-BPs. Our studies provide a molecular model of the eIF4E-eIF4G complex, shed light on the competition mechanism of 4E-BPs, and enable the rational design of selective eIF4G inhibitors to dampen dysregulated translation in disease.
authors: Department of Biochemistry, Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany.
authors: Stefan
authors: S
authors: Grüner
authors: Department of Biochemistry, Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany.
authors: Daniel
authors: D
authors: Peter
authors: Department of Biochemistry, Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany.
authors: Ramona
authors: R
authors: Weber
authors: Department of Biochemistry, Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany.
authors: Lara
authors: L
authors: Wohlbold
authors: Department of Biochemistry, Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany.
authors: Min-Yi
authors: MY
authors: Chung
authors: Department of Biochemistry, Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany. Electronic address: oliver.weichenrieder@tuebingen.mpg.de.
authors: Oliver
authors: O
authors: Weichenrieder
authors: Department of Biochemistry, Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany.
authors: Eugene
authors: E
authors: Valkov
authors: Department of Biochemistry, Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany.
authors: Cátia
authors: C
authors: Igreja
authors: Department of Biochemistry, Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany. Electronic address: elisa.izaurralde@tuebingen.mpg.de.
authors: Elisa
authors: E
authors: Izaurralde
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D039603:Eukaryotic Initiation Factor-4G / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D009154:Mutation; D010442:Peptide Chain Initiation, Translational; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics
chemical_list: D039561:Eukaryotic Initiation Factor-4E; D039603:Eukaryotic Initiation Factor-4G; D011994:Recombinant Proteins
keywords: 4E-BP; eIF4F; protein-protein interaction; translation initiation; translational inhibitors; translational regulation