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首页> 外文期刊>Molecular and Cellular Biology >The Rapamycin-Binding Domain Governs Substrate Selectivity by the Mammalian Target of Rapamycin
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The Rapamycin-Binding Domain Governs Substrate Selectivity by the Mammalian Target of Rapamycin

机译：雷帕霉素结合域通过雷帕霉素的哺乳动物靶标控制底物选择性

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The mammalian target of rapamycin (mTOR) is a Ser/Thr (S/T) protein kinase, which controls mRNA translation initiation by modulating phosphorylation of the translational regulators PHAS-I and p70S6K. Here we show that in vitro mTOR is able to phosphorylate these two regulators at comparable rates. Both (S/T)P sites, such as Thr36, Thr45, and Thr69 in PHAS-I and the h(S/T)h site (where h is a hydrophobic amino acid) Thr389 in p70S6K, were phosphorylated. Rapamycin-FKBP12 inhibited mTOR activity. Surprisingly, the extent of inhibition depended on the substrate. Moreover, mutating Ser2035 in the rapamycin-binding domain (FRB) not only decreased rapamycin sensitivity as expected but also dramatically affected the sites phosphorylated by mTOR. The results demonstrate that mutations in Ser2035 are not silent with respect to mTOR activity and implicate the FRB in substrate recognition. The findings also impose new limitations on interpreting results from experiments in which rapamycin and/or rapamycin-resistant forms of mTOR are used to investigate mTOR function in cells.
机译：雷帕霉素（mTOR）的哺乳动物靶标是Ser / Thr（S / T）蛋白激酶，它通过调节翻译调节因子PHAS-1和p70 S6K 的磷酸化来控制mRNA的翻译起始。在这里，我们显示了体外mTOR能够以可比的速率磷酸化这两种调节剂。 （S / T）P位点，例如PHAS-1中的Thr36，Thr45和Thr69，以及p70 S6K ，被磷酸化。雷帕霉素-FKBP12抑制mTOR活性。令人惊讶的是，抑制程度取决于底物。此外，突变雷帕霉素结合域（FRB）中的Ser2035不仅降低了雷帕霉素的敏感性，正如预期的那样，而且显着影响了mTOR磷酸化的位点。结果表明，Ser2035中的突变对于mTOR活性不是沉默的，并且暗示了FRB参与底物识别。这些发现还对解释雷帕霉素和/或雷帕霉素抗性形式的mTOR用于研究细胞中mTOR功能的实验的结果施加了新的限制。

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