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Molecular and Cellular Biology, January 2007, p. 147-156, Vol. 27, No. 1
0270-7306/07/$08.00+0     doi:10.1128/MCB.00867-06

Structural Basis for Inhibition of Translation by the Tumor Suppressor Pdcd4

Nicole LaRonde-LeBlanc,^1,* Arti N. Santhanam,^2, Alyson R. Baker,² Alexander Wlodawer,¹ and Nancy H. Colburn²

Macromolecular Crystallography Laboratory,¹ Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702²

Received 15 May 2006/ Returned for modification 8 August 2006/ Accepted 9 October 2006

The tumor suppressor function of Programmed Cell Death 4 (Pdcd4) is achieved through interactions between Pdcd4 and components of the translation initiation complex, namely, the RNA helicase eIF4A and the scaffolding protein eIF4G. These interactions are mediated through two MA3 domains on the Pdcd4 molecule and result in inhibition of protein synthesis. We have solved the high-resolution crystal structure of the C-terminal MA3 (cMA3) domain of Pdcd4 in several crystal forms and demonstrated its similarity to the MA3 domain of eIF4G. As predicted by the structure, the cMA3 domain competes with eIF4Gc for binding to eIF4A and surprisingly is sufficient to inhibit translation initiation. Mutations that abolish eIF4A binding negate both functions of the cMA3. Interestingly mutations in the Akt phosphorylation site influenced neither cMA3 binding to eIF4A nor its ability to inhibit translation initiation. Finally, our structural analysis reveals MA3 domains to be a novel subfamily of VHS domains.

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* Corresponding author. Mailing address: Macromolecular Crystallography Laboratory, CCR, National Cancer Institute, Frederick, MD 21702. Phone: (301) 405-0462. Fax: (301) 846-6322. E-mail: nlaronde{at}umd.edu.

Published ahead of print on 23 October 2006.

These authors contributed equally to this work.

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Molecular and Cellular Biology, January 2007, p. 147-156, Vol. 27, No. 1
0270-7306/07/$08.00+0     doi:10.1128/MCB.00867-06

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