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  current news   Press   selected story    
     
  13th February  
  Structural basis for translational inhibition by the tumor suppressor Pdcd4
 
 




Abstract
Portia G. Loh1,2, Hsin-Sheng Yang3, Martin A. Walsh4,  Qing Wang3, Xiaoxing Wang1, Zhihong Cheng1, Dingxiang Liu1,2, and Haiwei Song1,2

1 Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
2 Department of Biological Sciences, National University of Singapore, 14 Science Drive, Singapore 117543.
3 Graduate Center for Toxicology and Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY40536, USA.
4 MRC France, CRG BM14, ESRF, B.P.220, F-38043, Grenoble CEDEX, France.

Corresponding author: Haiwei Song, haiwei@imcb.a-star.edu.sg

Abstract
Pdcd4 is a tumor suppressor protein. It inhibits translation through interaction with translation initiator eIF4A, resulting in the suppression of neoplastic transformation and tumor 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 while 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.

 
 



Figure Legend: The structures of hPdcd4ΔN and the mPdcd4ΔN-eIF4A complex

A. Domain architecture of human/mouse Pdcd4 showing the putative N-terminal RNA-binding domain (purple), the N-terminal MA3 domain (nMA3; salmon), and the C-terminal MA3 domain (cMA3; blue). Numbers below the schematic protein outline represents the amino acid position for the domain boundaries.

B. Overall structure of hPdcd4ΔN. The ribbon diagrams of nMA3 and cMA3 are shown in salmon and blue, respectively.

C. Overall structure of the mPdcd4ΔN-eIF4A complex. The coloring scheme for nMA3 and cMA3 of Pdcd4, and the orientation of nMA3 are as in B. The two copies of eIF4A, eIF4A-A and eIF4A-D are shown in green and yellow, respectively. Individual domains are labeled.

D. Conformational change of Pdcd4 upon binding to eIF4A. Stereo views of the nMA3 of hPdcd4?N superimposed with that of mPdcd4ΔN in the mPdcd4ΔN-eIF4A complex. Pdcd4 in free form and in complex with eIF4A are shown in orange and blue, respectively, and two copies of eIF4A are shown in worm with the same colors as in C.

Published in The EMBO Journal advance online publication 15 January 2009; doi:10.1038/emboj.2008.278

For more information on A.Prof. Song Hai Wei’s lab, Please Click here.