The Library
Local control of a disorder-order transition in 4E-BP1 underpins regulation of translation via eIF4E
Tools
Tools
Tools
Tait, S., Dutta, K., Cowburn, D., Warwicker, J., Doig, A. J. and McCarthy, John E. G. (2010) Local control of a disorder-order transition in 4E-BP1 underpins regulation of translation via eIF4E. Proceedings of the National Academy of Sciences, Vol.107 (No.41). pp. 17627-17632. doi:10.1073/pnas.1008242107 ISSN 0027-8424.
Research output not available from this repository.
Request-a-Copy directly from author or use local Library Get it For Me service.
Official URL: http://dx.doi.org/10.1073/pnas.1008242107
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.
| Item Type: | Journal Article | ||||
|---|---|---|---|---|---|
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||
| Journal or Publication Title: | Proceedings of the National Academy of Sciences | ||||
| Publisher: | National Academy of Sciences | ||||
| ISSN: | 0027-8424 | ||||
| Official Date: | 2010 | ||||
| Dates: |
|
||||
| Volume: | Vol.107 | ||||
| Number: | No.41 | ||||
| Page Range: | pp. 17627-17632 | ||||
| DOI: | 10.1073/pnas.1008242107 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published |
Request changes or add full text files to a record
Repository staff actions (login required)
 |
View Item |
