Document Detail

Structural insights into the allosteric effects of 4EBP1 on the eukaryotic translation initiation factor eIF4E.
MedLine Citation:
PMID:  22178476     Owner:  NLM     Status:  MEDLINE    
The eukaryotic translation initiation factor eIF4E plays key roles in cap-dependent translation and mRNA export. These functions rely on binding the 7-methyl-guanosine moiety (5'cap) on the 5'-end of all mRNAs. eIF4E is regulated by proteins such as eIF4G and eIF4E binding proteins (4EBPs) that bind the dorsal surface of eIF4E, distal to the cap binding site, and modulate cap binding activity. Both proteins increase the affinity of eIF4E for 5'cap. Our understanding of the allosteric effects and structural underpinnings of 4EBP1 or eIF4G binding can be advanced by obtaining structural data on cap-free eIF4E bound to one of these proteins. Here, we report the crystal structure of apo-eIF4E and cap-free eIF4E in complex with a 4EBP1 peptide. We also monitored 4EBP1 binding to cap-free eIF4E in solution using NMR. Together, these studies suggest that 4EBP1 transforms eIF4E into a cap-receptive state. NMR methods were also used to compare the allosteric routes activated by 4EBP1, eIF4G, and the arenavirus Z protein, a negative regulator of cap binding. We observed chemical shift perturbation at the dorsal binding site leading to alterations in the core of the protein, which were ultimately communicated to the unoccupied cap binding site of eIF4E. There were notable similarities between the routes taken by 4EBP1 and eIF4G and differences from the negative regulator Z. Thus, binding of 4EBP1 or eIF4G allosterically drives alterations throughout the protein that increase the affinity of eIF4E for the 5'cap.
Nadeem Siddiqui; Wolfram Tempel; Lucy Nedyalkova; Laurent Volpon; Amy K Wernimont; Michael J Osborne; Hee-Won Park; Katherine L B Borden
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2011-12-09
Journal Detail:
Title:  Journal of molecular biology     Volume:  415     ISSN:  1089-8638     ISO Abbreviation:  J. Mol. Biol.     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-01-27     Completed Date:  2012-03-21     Revised Date:  2014-09-12    
Medline Journal Info:
Nlm Unique ID:  2985088R     Medline TA:  J Mol Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  781-92     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Elsevier Ltd. All rights reserved.
Data Bank Information
Bank Name/Acc. No.:
PDB/3TF2;  3U7X
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MeSH Terms
Adaptor Proteins, Signal Transducing / chemistry*,  metabolism
Allosteric Regulation
Crystallography, X-Ray
DNA-Binding Proteins / chemistry*,  metabolism
Phosphoproteins / chemistry*,  metabolism
Protein Binding
Protein Conformation
RNA Caps / chemistry,  metabolism
Transcription Factors / chemistry*,  metabolism
Grant Support
R01 98571//PHS HHS; R01 CA098571/CA/NCI NIH HHS; R01 CA098571-07/CA/NCI NIH HHS; R01 CA098571-08/CA/NCI NIH HHS; R01 CA098571-09/CA/NCI NIH HHS; //Canadian Institutes of Health Research
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/DNA-Binding Proteins; 0/EIF4EBP1 protein, human; 0/ELF4 protein, human; 0/Phosphoproteins; 0/RNA Caps; 0/Transcription Factors

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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