Structural basis for translational inhibition by the tumour suppressor Pdcd4
Open Access
- 15 January 2009
- journal article
- research article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 28 (3), 274-285
- https://doi.org/10.1038/emboj.2008.278
Abstract
Pdcd4 is a tumour suppressor protein. It inhibits translation through interaction with translation initiator eIF4A, resulting in the suppression of neoplastic transformation and tumour invasion. Here, we present the crystal structures of an N‐terminal‐truncated Pdcd4 in free form and in complex with eIF4A. Upon binding to eIF4A, Pdcd4 undergoes a marked conformational change to form a heterotrimeric complex with eIF4A, with one Pdcd4 binding to two eIF4A molecules in two different modes. The binding of Pdcd4 to eIF4A is required to inhibit the enzymatic activity of eIF4A, translation initiation, and AP‐1‐dependent transcription. Both MA3 domains are required to efficiently compete with the C‐terminal domain of eIF4G (eIF4Gc) for binding to eIF4A whereas a single MA3 is sufficient to inhibit translation. Our structural and mutational analyses reveal that Pdcd4 inhibits translation initiation by trapping eIF4A in an inactive conformation, and blocking its incorporation into the eIF4F complex.This publication has 48 references indexed in Scilit:
- Crystal structure of the yeast eIF4A-eIF4G complex: An RNA-helicase controlled by protein–protein interactionsProceedings of the National Academy of Sciences of the United States of America, 2008
- PDCD4 inhibits translation initiation by binding to eIF4A using both its MA3 domainsProceedings of the National Academy of Sciences of the United States of America, 2008
- Anti-inflammatory lipid mediator 15d-PGJ2 inhibits translation through inactivation of eIF4AThe EMBO Journal, 2007
- Phasercrystallographic softwareJournal of Applied Crystallography, 2007
- Functional characterization of IRESes by an inhibitor of the RNA helicase eIF4ANature Chemical Biology, 2006
- Coot: model-building tools for molecular graphicsActa crystallographica. Section D, Structural biology, 2004
- Induction of PDCD4 tumor suppressor gene expression by RAR agonists, antiestrogen and HER-2/neu antagonist in breast cancer cells. Evidence for a role in apoptosisOncogene, 2004
- Size-Distribution Analysis of Macromolecules by Sedimentation Velocity Ultracentrifugation and Lamm Equation ModelingBiophysical Journal, 2000
- Refinement of Macromolecular Structures by the Maximum-Likelihood MethodActa crystallographica. Section D, Structural biology, 1997
- The CCP4 suite: programs for protein crystallographyActa crystallographica. Section D, Structural biology, 1994