ArticleNature2015
Folding of an intrinsically disordered protein by phosphorylation as a regulatory switch.
Article in Nature, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 301 papers.
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Who cites it
301 citing papers in PubMed, 562 citations in OpenAlex.
- Drude polarizable force field for phosphorylated polypeptides and proteins.Biophysical journal · 2026Article
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- Distinct phosphorylation mechanisms as dynamic switches for Hsp90 regulation.Nature communications · 2026Article
- Structural mechanism for noncanonical GPCR signaling in the Hedgehog pathway.Nature structural & molecular biology · 2026Article
- mTORC1 and nuclear ERK spatially control translation in cardiomyocytes through 4EBP1 phosphorylation.Science signaling · 2026Article
- Impact of Ser81 phosphorylation on alanine: glyoxylate aminotransferase associated with Primary hyperoxaluria type I.Molecular biomedicine · 2026Article
- Deciphering How Clustered O‑Glycosylation Shapes Substrate-Binding Preferences in an Intrinsically Disordered Protein Region.JACS Au · 2026Article
- A Survey of Predicted Protein-Protein Interactions Involving Disordered Regions in Humans.Journal of molecular biology · 2026Article
- Decoding the Post-translational Modification Crosstalk: Functional Implications of Phosphorylation, Acetylation, and Methylation.The journal of physical chemistry. B · 2026Article
- 4E-BP2-dependent translational control in GABAergic interneurons is required for long-term memory.Molecular neurobiology · 2026Article
- Preparation of a Magnetic Ti-IMAC Material Based on Thiol-Ene Click Reaction and the Application in Intact Phosphoprotein Enrichment.Molecules (Basel, Switzerland) · 2026Article
- Novel LncRNA Gm44763 Regulates Morphine-Induced Reward Memory via MiR-298-5p-Mediated eIF4E Translation Control.Research (Washington, D.C.) · 2026Article
- AlphaFlex: Ensembles of the human proteome representing disordered regions.bioRxiv : the preprint server for biology · 2025Article
- Cell Type-Specific mTORC1 Signaling and Translational Control in Synaptic Plasticity and Memory.Journal of neurochemistry · 2025Review
- Navigating the landscape of protein folding and proteostasis: from molecular chaperones to therapeutic innovations.Signal transduction and targeted therapy · 2025Review
- Biological insights from integrative modeling of intrinsically disordered protein systems.Current opinion in structural biology · 2025Review
- Translational reprogramming under heat stress: a plant's perspective.Royal Society open science · 2025Review
- 'Intelligent' proteins.Cellular and molecular life sciences : CMLS · 2025Review
- 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
241 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
Intrinsically disordered proteins play important roles in cell signalling, transcription, translation and cell cycle regulation. Although they lack stable tertiary structure, many intrinsically disordered proteins undergo disorder-to-order transitions upon binding to partners. Similarly, several folded proteins use regulated order-to-disorder transitions to mediate biological function. In principle, the function of intrinsically disordered proteins may be controlled by post-translational modifications that lead to structural changes such as folding, although this has not been observed. Here we show that multisite phosphorylation induces folding of the intrinsically disordered 4E-BP2, the major neural isoform of the family of three mammalian proteins that bind eIF4E and suppress cap-dependent translation initiation. In its non-phosphorylated state, 4E-BP2 interacts tightly with eIF4E using both a canonical YXXXXLΦ motif (starting at Y54) that undergoes a disorder-to-helix transition upon binding and a dynamic secondary binding site. We demonstrate that phosphorylation at T37 and T46 induces folding of residues P18-R62 of 4E-BP2 into a four-stranded β-domain that sequesters the helical YXXXXLΦ motif into a partly buried β-strand, blocking its accessibility to eIF4E. The folded state of pT37pT46 4E-BP2 is weakly stable, decreasing affinity by 100-fold and leading to an order-to-disorder transition upon binding to eIF4E, whereas fully phosphorylated 4E-BP2 is more stable, decreasing affinity by a factor of approximately 4,000. These results highlight stabilization of a phosphorylation-induced fold as the essential mechanism for phospho-regulation of the 4E-BP:eIF4E interaction and exemplify a new mode of biological regulation mediated by intrinsically disordered proteins.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.