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The regulation mechanism of phosphorylation and mutations in intrinsically disordered protein 4E-BP2

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Abstract

Eukaryotic translation initiation factor 4E binding protein 2 (4E-BP2) is an inhibitor of mRNA cap-dependent translations. Wild-type (WT) 4E-BP2 is intrinsically disordered under physiological conditions, while phosphorylation converts the disordered fragments 18–62 into a four-stranded β-sheet structure. The regulation mechanism of phosphorylation on 4E-BP2 still remains ambiguous. In this study, replica-exchange molecular dynamics (REMD) simulations were utilized to sample the conformation spaces of WT, phosphorylated WT (pWT), and phosphorylated mutated (pMT) 4E-BP2. Starting from extended structures, the folded structures were only observed in pWT simulations. The folding pathway shows that the folded structures of pWT are formed in the order of β1/β4, β3, and β2. The formation of β-turns on pWT, which are driven by hydrogen bonds between the phosphorylated residues and adjacent residues, are the rate-limiting steps in the folding process. The long-range electrostatic interactions contribute toward the stabilization of the folded structures. Moreover, the disruption of β-turn structures induced by mutations would prevent the folding of pMT 4E-BP2. Our finding is helpful in understanding the regulation of the structural ensembles of intrinsically disordered proteins.

Graphical abstract: The regulation mechanism of phosphorylation and mutations in intrinsically disordered protein 4E-BP2

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Article information


Submitted
30 Oct 2019
Accepted
24 Dec 2019
First published
26 Dec 2019

Phys. Chem. Chem. Phys., 2020, Advance Article
Article type
Paper

The regulation mechanism of phosphorylation and mutations in intrinsically disordered protein 4E-BP2

K. Wang, S. Ning, Y. Guo, M. Duan and M. Yang, Phys. Chem. Chem. Phys., 2020, Advance Article , DOI: 10.1039/C9CP05888E

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