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Non-cooperative 4E-BP2 folding with exchange between eIF4E-binding and binding-incompatible states tunes cap-dependent translation inhibition.
- Source :
-
Nature communications [Nat Commun] 2020 Jun 19; Vol. 11 (1), pp. 3146. Date of Electronic Publication: 2020 Jun 19. - Publication Year :
- 2020
-
Abstract
- Phosphorylation of intrinsically disordered eIF4E binding proteins (4E-BPs) regulates cap-dependent translation by weakening their ability to compete with eIF4G for eIF4E binding within the translation initiation complex. We previously showed that phosphorylation of T37 and T46 in 4E-BP2 induces folding of a four-stranded beta-fold domain, partially sequestering the canonical eIF4E-binding helix. The C-terminal intrinsically disordered region (C-IDR), remaining disordered after phosphorylation, contains the secondary eIF4E-binding site and three other phospho-sites, whose mechanisms in inhibiting binding are not understood. Here we report that the domain is non-cooperatively folded, with exchange between beta strands and helical conformations. C-IDR phosphorylation shifts the conformational equilibrium, controlling access to eIF4E binding sites. The hairpin turns formed by pT37/pT46 are remarkably stable and function as transplantable units for phospho-regulation of stability. These results demonstrate how non-cooperative folding and conformational exchange leads to graded inhibition of 4E-BP2:eIF4E binding, shifting 4E-BP2 into an eIF4E binding-incompatible conformation and regulating translation initiation.
- Subjects :
- Computational Biology
Eukaryotic Initiation Factor-4E genetics
Intrinsically Disordered Proteins genetics
Mutagenesis, Site-Directed
Nuclear Magnetic Resonance, Biomolecular
Phosphorylation physiology
Protein Binding genetics
Protein Conformation, alpha-Helical genetics
Protein Conformation, beta-Strand genetics
Protein Folding
Protein Processing, Post-Translational physiology
Eukaryotic Initiation Factor-4E metabolism
Intrinsically Disordered Proteins metabolism
Protein Biosynthesis physiology
RNA Caps metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 11
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 32561718
- Full Text :
- https://doi.org/10.1038/s41467-020-16783-8