Journal
MOLECULAR CELL
Volume 81, Issue 11, Pages 2403-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2021.03.031
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Funding
- Swiss National Science Foundation [159696, 179323, 179569]
- Innosuisse grant [28452.1]
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The study reveals that mTORC1 achieves hierarchical phosphorylation of 4E-BP1 through specific interactions, facilitating efficient activation of translation. Furthermore, mTORC1 is capable of recognizing both free and eIF4E-bound 4E-BP1, enabling rapid phosphorylation of the entire 4E-BP1 pool.
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.
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