Structural basis for inhibition of translation by the tumor suppressor Pdcd4
Structural basis for inhibition of translation by the tumor suppressor Pdcd4
复制标题
DOI：
10.1128/mcb.00867-06
复制
发表时间：
2007-01-01
影响因子：
5.3
通讯作者：
Colburn, Nancy H.
中科院分区：
文献类型：
--
作者：
LaRonde-LeBlanc, Nicole;Santhanam, Arti N.;Colburn, Nancy H.
程序性细胞死亡4（Pdcd 4）的肿瘤抑制功能是通过Pdcd 4和翻译起始复合物的组分（即RNA解旋酶eIF 4A和支架蛋白eIF 4G）之间的相互作用实现的。这些相互作用通过Pdcd 4分子上的两个MA 3结构域介导，并导致蛋白质合成的抑制。我们已经解决了几种晶体形式的Pdcd 4的C-末端MA 3（cMA 3）结构域的高分辨率晶体结构，并证明了其与eIF 4G的MA 3结构域的相似性。如结构所预测的，cMA 3结构域与eIF 4Gc竞争结合eIF 4A，并且令人惊讶地足以抑制翻译起始。消除eIF 4A结合的突变否定了cMA 3的两种功能。有趣的是，Akt磷酸化位点的突变既不影响cMA 3与eIF 4A的结合，也不影响其抑制翻译起始的能力。最后，我们的结构分析表明MA 3域是一个新的亚家族的VHS域。
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.