ArticleProceedings of the National Academy of Sciences of the United States of America2010
Local control of a disorder-order transition in 4E-BP1 underpins regulation of translation via eIF4E.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed.
- An electrostatic network with strong connectivity is a phospho-sensor for regulating affinity of Syk-receptor association.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Chemical Probes for Studying the Eukaryotic Translation Initiation Factor 4E (eIF4E)-Regulated Translatome in Cancer.ACS pharmacology & translational science · 2025Review
- Delineating Structural Propensities of the 4E-BP2 Protein via Integrative Modeling and Clustering.The journal of physical chemistry. B · 2023Article
- Multisite phosphorylation and binding alter conformational dynamics of the 4E-BP2 protein.Biophysical journal · 2022Article
- OTS167 blocks FLT3 translation and synergizes with FLT3 inhibitors in FLT3 mutant acute myeloid leukemia.Blood cancer journal · 2021Article
- A cell-penetrant lactam-stapled peptide for targeting eIF4E protein-protein interactions.European journal of medicinal chemistry · 2020Article
- Non-cooperative 4E-BP2 folding with exchange between eIF4E-binding and binding-incompatible states tunes cap-dependent translation inhibition.Nature communications · 2020Article
- Characterizing Post-Translational Modifications and Their Effects on Protein Conformation Using NMR Spectroscopy.Biochemistry · 2020Review
- Consideration of Binding Kinetics in the Design of Stapled Peptide Mimics of the Disordered Proteins Eukaryotic Translation Initiation Factor 4E-Binding Protein 1 and Eukaryotic Translation Initiation Factor 4G.Journal of medicinal chemistry · 2019Article
- The Leishmania PABP1-eIF4E4 interface: a novel 5'-3' interaction architecture for trans-spliced mRNAs.Nucleic acids research · 2019Article
- A Conditionally Fluorescent Peptide Reporter of Secondary Structure Modulation.Chembiochem : a European journal of chemical biology · 2019Article
- Ribosomal RACK1:Protein Kinase C βII Modulates Intramolecular Interactions between Unstructured Regions of Eukaryotic Initiation Factor 4G (eIF4G) That Control eIF4E and eIF3 Binding.Molecular and cellular biology · 2018Article
- Dynamic Protein Interaction Networks and New Structural Paradigms in Signaling.Chemical reviews · 2016Review
- Article
- Post-translationally-modified structures in the autophagy machinery: an integrative perspective.The FEBS journal · 2015Review
- Folding of an intrinsically disordered protein by phosphorylation as a regulatory switch.Nature · 2015Article
- Effect of temperature on the conformation of natively unfolded protein 4E-BP1 in aqueous and mixed solutions containing trifluoroethanol and hexafluoroisopropanol.The protein journal · 2015Article
- Assessment of mTOR-Dependent Translational Regulation of Interferon Stimulated Genes.PloS one · 2015Article
- Global discovery of high-NaCl-induced changes of protein phosphorylation.American journal of physiology. Cell physiology · 2014Article
- Physicochemical properties of cells and their effects on intrinsically disordered proteins (IDPs).Chemical reviews · 2014Review
Corrections and comments
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Authors and funding
6 authors.
Funding
Abstract
The molecular mechanism underpinning regulation of eukaryotic translation initiation factor eIF4E by 4E-BP1 has remained unclear. We use isothermal calorimetry, circular dichroism, NMR, and computational modeling to analyze how the structure of the eIF4E-binding domain of 4E-BP1 determines its affinity for the dorsal face of eIF4E and thus the ability of this regulator to act as a competitive inhibitor. This work identifies the key role of solvent-facing amino acids in 4E-BP1 that are not directly engaged in interactions with eIF4E. These amino acid residues influence the propensity of the natively unfolded binding motif to fold into a conformation, including a stretch of α-helix, that is required for tight binding to eIF4E. In so doing, they contribute to a free energy landscape for 4E-BP1 folding that is poised so that phosphorylation of S65 at the C-terminal end of the helical region can modulate the propensity of folding, and thus regulate the overall free energy of 4E-BP1 binding to eIF4E, over a physiologically significant range. Thus, phosphorylation acts as an intramolecular structural modulator that biases the free energy landscape for the disorder-order transition of 4E-BP1 by destabilizing the α-helix to favor the unfolded form that cannot bind eIF4E. This type of order-disorder regulatory mechanism is likely to be relevant to other intermolecular regulatory phenomena in the cell.
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