Loh Portia G, Yang Hsin-Sheng, Walsh Martin A, Wang Qing, Wang Xiaoxing, Cheng Zhihong, Liu Dingxiang, Song Haiwei
Institute of Molecular and Cell Biology, Proteos, Singapore.
EMBO J. 2009 Feb 4;28(3):274-85. doi: 10.1038/emboj.2008.278. Epub 2009 Jan 15.
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.
Pdcd4是一种肿瘤抑制蛋白。它通过与翻译起始因子eIF4A相互作用来抑制翻译，从而抑制肿瘤转化和肿瘤侵袭。在此，我们展示了N端截短的Pdcd4的游离形式以及与eIF4A形成复合物的晶体结构。与eIF4A结合后，Pdcd4发生显著的构象变化，与eIF4A形成异源三聚体复合物，一个Pdcd4以两种不同模式与两个eIF4A分子结合。Pdcd4与eIF4A的结合对于抑制eIF4A的酶活性、翻译起始以及AP-1依赖的转录是必需的。两个MA3结构域对于与eIF4G的C端结构域（eIF4Gc）有效竞争结合eIF4A是必需的，而单个MA3结构域就足以抑制翻译。我们的结构和突变分析表明，Pdcd4通过将eIF4A捕获在无活性构象中并阻止其掺入eIF4F复合物来抑制翻译起始。
