25-30 August 2019
Henry Ford Building
Europe/Berlin timezone

The dynamic mechanism of 4E-BP1 recognition by mTORC1

Not scheduled
4h
Harnack House and Henry Ford Building

Harnack House and Henry Ford Building

Board: 179
Poster Posters

Speaker

Prof. Sebastian Hiller (Biozentrum, University of Basel, Switzerland)

Description

Translation of proteins is a crucial cellular process that requires tight regulation. In eukaryotes, its activation requires phosphorylation of the cellular pool of the intrinsically disordered protein 4E-BP1. This is achieved by the 1 MDa kinase complex mTORC1 (mammalian Target of Rapamycin Complex 1), a central cellular signaling hub that integrates multiple signaling pathways. mTORC1 thus needs to combine substrate specificity with efficient processing speed. Phosphorylation of 4E-BP1 leads to release of eIF4E, initiating translation.
Here, we monitor 4E-BP1 by solution NMR spectroscopy while it is interacting with mTORC1 or its subunit Raptor to resolve mechanistic details of the substrate recognition and its regulation. 4E-BP1 binds to Raptor via two interaction sites at its N- and C-terminus, tethering the substrate specifically to mTORC1 but leaving flexibility in its central region to allow the kinase reaching multiple phosphorylation sites. Furthermore, we demonstrate that Raptor and mTORC1 not only bind apo 4E-BP1, but also the fully assembled 4E-BP1:eIF4E complex, as well as phosphorylated 4E-BP1. This multi-species recognition is enabled by the spatial separation of recognition and phosphorylation sites. Importantly, the recognition of the 4E-BP1:eIF4E complex ensures that the cellular pool of 4E-BP1 can be efficiently phosphorylated, not limited by the slow release kinetics of 4E-BP1 from eIF4E, enabling an overall rapid signalling response.

Primary authors

Prof. Sebastian Hiller (Biozentrum, University of Basel, Switzerland) Prof. Timm Maier (Biozentrum, University of Basel, Switzerland) Dr Raphael Böhm (Biozentrum, University of Basel, Switzerland) Dr Stefan Imseng (Biozentrum, University of Basel, Switzerland) Dr Roman A. Jakob (Biozentrum, University of Basel, Switzerland)

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