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

Cátia Igreja, Daniel Peter, Catrin Weiler and Elisa Izaurralde ()
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Cátia Igreja: Max Planck Institute for Developmental Biology
Daniel Peter: Max Planck Institute for Developmental Biology
Catrin Weiler: Max Planck Institute for Developmental Biology
Elisa Izaurralde: Max Planck Institute for Developmental Biology

Nature Communications, 2014, vol. 5, issue 1, 1-14

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5790

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