Deciphering the mechanistic effects of eIF4E phosphorylation on mRNA‐cap recognition

Deciphering the mechanistic effects of eIF4E phosphorylation on mRNA‐cap recognition
Title:
Deciphering the mechanistic effects of eIF4E phosphorylation on mRNA‐cap recognition
Other Titles:
Protein Science
Publication Date:
06 December 2019
Citation:
Lama, D, Verma, CS. Deciphering the mechanistic effects of eIF4E phosphorylation on mRNA‐cap recognition. Protein Science. 2019; 1– 14. https://doi.org/10.1002/pro.3798
Abstract:
The mRNA cap‐binding oncoprotein “eIF4E” is phosphorylated at residue S209 by Mnk kinases, and is closely associated with tumor development and progression. Despite being well‐established, mechanistic details at the molecular level of mRNA recognition by eIF4E due to phosphorylation have not been clearly elucidated. We investigated this through molecular modeling and simulations of the S209 phosphorylated derivative of eIF4E and explored the associated implication on the binding of the different variants of mRNA‐cap analogs. A key feature that emerges as a result of eIF4E phosphorylation is a salt‐bridge network between the phosphorylated S209 (pS209) and a specific pair of lysine residues (K159 and K162) within the cap‐binding interface on eIF4E. This interaction linkage stabilizes the otherwise dynamic C‐terminal region of the protein, resulting in the attenuation of the overall plasticity and accessibility of the binding pocket. The pS209‐K159 salt‐bridge also results in an energetically less favorable environment for the bound mRNA‐cap primarily due to electrostatic repulsion between the negative potentials from the phosphates in the cap and those appearing as a result of phosphorylation of S209. These observations collectively imply that the binding of the mRNA‐cap will be adversely affected in the phosphorylated derivative of eIF4E. We propose a mechanistic model highlighting the role of eIF4E phosphorylation as a regulatory tool in modulating eIF4E: mRNA‐cap recognition and its potential impact on translation initiation.
License type:
PublisherCopyrights
Funding Info:
BMRC (A*STAR) Singapore. Grant Number: IAF111213C
Description:
This is the peer reviewed version of the following article: Lama, D, Verma, CS. Deciphering the mechanistic effects of eIF4E phosphorylation on mRNA‐cap recognition. Protein Science. 2019; 1– 14. https://doi.org/10.1002/pro.3798, which has been published in final form at https://doi.org/10.1002/pro.3798. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
ISSN:
0961-8368
1469-896X
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