Structural basis for inhibition of translation by the tumor suppressor Pdcd4

被引:64
作者
LaRonde-LeBlanc, Nicole [1 ]
Santhanam, Arti N.
Baker, Alyson R.
Wlodawer, Alexander
Colburn, Nancy H.
机构
[1] NCI, Macromol Crystallog Lab, CCR, Frederick, MD 21702 USA
[2] NCI, Lab Canc Prevent, Canc Res Ctr, Frederick, MD 21702 USA
关键词
D O I
10.1128/MCB.00867-06
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:147 / 156
页数:10
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