The dynamic mechanism of 4E-BP1 recognition and phosphorylation by mTORC1.
Mol Cell
; 81(11): 2403-2416.e5, 2021 06 03.
Article
en En
| MEDLINE
| ID: mdl-33852892
ABSTRACT
The activation of cap-dependent translation in eukaryotes requires multisite, hierarchical phosphorylation of 4E-BP by the 1 MDa kinase mammalian target of rapamycin complex 1 (mTORC1). To resolve the mechanism of this hierarchical phosphorylation at the atomic level, we monitored by NMR spectroscopy the interaction of intrinsically disordered 4E binding protein isoform 1 (4E-BP1) with the mTORC1 subunit regulatory-associated protein of mTOR (Raptor). The N-terminal RAIP motif and the C-terminal TOR signaling (TOS) motif of 4E-BP1 bind separate sites in Raptor, resulting in avidity-based tethering of 4E-BP1. This tethering orients the flexible central region of 4E-BP1 toward the mTORC1 kinase site for phosphorylation. The structural constraints imposed by the two tethering interactions, combined with phosphorylation-induced conformational switching of 4E-BP1, explain the hierarchy of 4E-BP1 phosphorylation by mTORC1. Furthermore, we demonstrate that mTORC1 recognizes both free and eIF4E-bound 4E-BP1, allowing rapid phosphorylation of the entire 4E-BP1 pool and efficient activation of translation. Finally, our findings provide a mechanistic explanation for the differential rapamycin sensitivity of the 4E-BP1 phosphorylation sites.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Proteínas de Ciclo Celular
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Factor 4E Eucariótico de Iniciación
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Proteínas Adaptadoras Transductoras de Señales
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Serina-Treonina Quinasas TOR
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Diana Mecanicista del Complejo 1 de la Rapamicina
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Proteína Reguladora Asociada a mTOR
Tipo de estudio:
Prognostic_studies
Idioma:
En
Año:
2021
Tipo del documento:
Article