mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events
mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events
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DOI：
10.1016/j.cell.2005.10.024
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发表时间：
2005-11-08
期刊：
影响因子：
64.5
通讯作者：
Blenis, J
中科院分区：
文献类型：
--
作者：
Holz, MK;Ballif, BA;Blenis, J
为了响应营养素、能量充足、激素和促有丝分裂剂，S6 K1磷酸化与翻译相关的几个靶点。然而，S6 K1被激活，遇到底物，并有助于翻译起始的分子机制知之甚少。我们发现，mTOR和S6 K1操纵和关闭真核生物起始因子3（eIF 3）翻译起始复合物的信号依赖性，编排的方式。当失活时，S6 K1与eIF 3复合物结合，而S6 K1激活剂mTOR/raptor不结合。细胞刺激促进mTOR/raptor与eIF 3复合物的结合以及S6 K1在其疏水基序处的磷酸化。磷酸化导致S6 K1解离、活化，随后磷酸化其翻译靶标，包括eIF 4 B，然后以磷酸化依赖性方式募集到复合物中。因此，eIF 3前起始复合物作为一个支架，以协调一个动态的事件序列，以响应刺激，促进有效的蛋白质合成。
In response to nutrients, energy sufficiency, hormones, and mitogenic agents, S6K1 phosphorylates several targets linked to translation. However, the molecular mechanisms whereby S6K1 is activated, encounters substrate, and contributes to translation initiation are poorly understood. We show that mTOR and S6K1 maneuver on and off the eukaryotic initiation factor 3 (eIF3) translation initiation complex in a signal-dependent, choreographed fashion. When inactive, S6K1 associates with the eIF3 complex, while the S6K1 activator mTOR/raptor does not. Cell stimulation promotes mTOR/raptor binding to the eIF3 complex and phosphorylation of S6K1 at its hydrophobic motif. Phosphorylation results in S6K1 dissociation, activation, and subsequent phosphorylation of its translational targets, including eIF4B, which is then recruited into the complex in a phosphorylation-dependent manner. Thus, the eIF3 preinitiation complex acts as a scaffold to coordinate a dynamic sequence of events in response to stimuli that promote efficient protein synthesis.