4E-BPs require non-canonical 4E-binding motifs and a lateral surface of eIF4E to repress translation

Nat Commun. 2014 Sep 2:5:4790. doi: 10.1038/ncomms5790.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Binding Sites
  • Binding, Competitive
  • Drosophila Proteins / chemistry*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / genetics*
  • Drosophila melanogaster / metabolism
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Eukaryotic Initiation Factor-4E / chemistry*
  • Eukaryotic Initiation Factor-4E / genetics
  • Eukaryotic Initiation Factor-4E / metabolism
  • Eukaryotic Initiation Factor-4G / chemistry*
  • Eukaryotic Initiation Factor-4G / genetics
  • Eukaryotic Initiation Factor-4G / metabolism
  • Gene Expression Regulation
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Binding
  • Protein Biosynthesis
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism

Substances

  • Drosophila Proteins
  • Eukaryotic Initiation Factor-4E
  • Eukaryotic Initiation Factor-4G
  • Recombinant Proteins
  • cup protein, Drosophila