title: 4E-BPs require non-canonical 4E-binding motifs and a lateral surface of eIF4E to repress translation.
abstract: eIF4E-binding proteins (4E-BPs) are a widespread class of translational regulators that share a canonical (C) eIF4E-binding motif (4E-BM) with eIF4G. Consequently, 4E-BPs compete with eIF4G for binding to the dorsal surface on eIF4E to inhibit translation initiation. Some 4E-BPs contain non-canonical 4E-BMs (NC 4E-BMs), but the contribution of these motifs to the repressive mechanism--and whether these motifs are present in all 4E-BPs--remains unknown. Here, we show that the three annotated Drosophila melanogaster 4E-BPs contain NC 4E-BMs. These motifs bind to a lateral surface on eIF4E that is not used by eIF4G. This distinct molecular recognition mode is exploited by 4E-BPs to dock onto eIF4E-eIF4G complexes and effectively displace eIF4G from the dorsal surface of eIF4E. Our data reveal a hitherto unrecognized role for the NC4E-BMs and the lateral surface of eIF4E in 4E-BP-mediated translational repression, and suggest that bipartite 4E-BP mimics might represent efficient therapeutic tools to dampen translation during oncogenic transformation.
authors.affiliation: Department of Biochemistry, Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany.
authors.forename: Cátia
authors.initials: C
authors.lastname: Igreja
authors.affiliation: Department of Biochemistry, Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Peter
authors.affiliation: Department of Biochemistry, Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany.
authors.forename: Catrin
authors.initials: C
authors.lastname: Weiler
authors.affiliation: Department of Biochemistry, Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany.
authors.forename: Elisa
authors.initials: E
authors.lastname: Izaurralde
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D029721:Drosophila Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; 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; D005786:Gene Expression Regulation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D014176:Protein Biosynthesis; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D039561:Eukaryotic Initiation Factor-4E; D039603:Eukaryotic Initiation Factor-4G; D011994:Recombinant Proteins; C105238:cup protein, Drosophila