The Structures of eIF4E-eIF4G Complexes Reveal an Extended Interface to Regulate Translation Initiation.
Mol Cell
; 64(3): 467-479, 2016 11 03.
Article
em En
| MEDLINE
| ID: mdl-27773676
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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Iniciação Traducional da Cadeia Peptídica
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Fator de Iniciação 4E em Eucariotos
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Fator de Iniciação Eucariótico 4G
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Drosophila melanogaster
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article