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The Structures of eIF4E-eIF4G Complexes Reveal an Extended Interface to Regulate Translation Initiation

MPS-Authors
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Grüner,  S
Department Biochemistry, Max Planck Institute for Developmental Biology, Max Planck Society;

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Peter,  D
Department Biochemistry, Max Planck Institute for Developmental Biology, Max Planck Society;

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Weber,  R
Department Biochemistry, Max Planck Institute for Developmental Biology, Max Planck Society;

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Wohlbold,  L
Department Biochemistry, Max Planck Institute for Developmental Biology, Max Planck Society;

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Chung,  M-Y
Department Biochemistry, Max Planck Institute for Developmental Biology, Max Planck Society;

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Weichenrieder,  O
Department Biochemistry, Max Planck Institute for Developmental Biology, Max Planck Society;
Retrotransposition and Regulatory RNAs Group, Department Biochemistry, Max Planck Institute for Developmental Biology, Max Planck Society;

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Valkov,  E
Department Biochemistry, Max Planck Institute for Developmental Biology, Max Planck Society;

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Igreja,  C
Department Biochemistry, Max Planck Institute for Developmental Biology, Max Planck Society;
Regulation and Post-Translational Modification of Gene Expression in Nematodes Group, Department Integrative Evolutionary Biology, Max Planck Institute for Developmental Biology, Max Planck Society;

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Izaurralde,  E
Department Biochemistry, Max Planck Institute for Developmental Biology, Max Planck Society;

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Citation

Grüner, S., Peter, D., Weber, R., Wohlbold, L., Chung, M.-Y., Weichenrieder, O., et al. (2016). The Structures of eIF4E-eIF4G Complexes Reveal an Extended Interface to Regulate Translation Initiation. Molecular Cell, 64(3), 467-479. doi:10.1016/j.molcel.2016.09.020.


Cite as: https://hdl.handle.net/21.11116/0000-000A-7F19-D
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.