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首页> 外文期刊>Genes to cells : >Dissociation of raptor from mTOR is a mechanism of rapamycin-induced inhibition of mTOR function.
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Dissociation of raptor from mTOR is a mechanism of rapamycin-induced inhibition of mTOR function.

机译：猛禽与mTOR的分离是雷帕霉素诱导的mTOR功能抑制的机制。

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摘要

The mammalian target of rapamycin (mTOR) is a Ser/Thr protein kinase that plays a crucial role in a nutrient-sensitive signalling pathway that regulates cell growth. TOR signalling is potently inhibited by rapamycin, through the direct binding of a FK506-binding protein 12 (FKBP12)/rapamycin complex to the TOR FRB domain, a segment amino terminal to the kinase catalytic domain. The molecular basis for the inhibitory action of FKBP12/rapamycin remains uncertain. Raptor (regulatory associated protein of mTOR) is a recently identified mTOR binding partner that is essential for mTOR signalling in vivo, and whose binding to mTOR is critical for mTOR-catalysed substrate phosphorylation in vitro. Here we investigated the stability of endogenous mTOR/raptor complex in response to rapamycin in vivo, and to the direct addition of a FKBP12/rapamycin complex in vitro. Rapamycin diminished the recovery of endogenous raptor with endogenous or recombinant mTOR in vivo; this inhibition required the ability of mTOR to bind the FKBP12/rapamycin complex, but was independent of mTOR kinase activity. Rapamycin, in the presence of FKBP12, inhibited the association of raptor with mTOR directly in vitro, and concomitantly reduced the mTOR-catalysed phosphorylation of raptor-dependent, but not raptor-independent substrates; mTOR autophosphorylation was unaltered. These observations indicate that rapamycin inhibits mTOR function, at least in part, by inhibiting the interaction of raptor with mTOR; this action uncouples mTOR from its substrates, and inhibits mTOR signalling without altering mTOR's intrinsic catalytic activity.
机译：雷帕霉素（mTOR）的哺乳动物靶标是Ser / Thr蛋白激酶，在调节细胞生长的营养敏感信号通路中起关键作用。通过FK506结合蛋白12（FKBP12）/雷帕霉素复合物与TOR FRB结构域（激酶催化结构域的氨基末端区段）的直接结合，雷帕霉素可有效抑制TOR信号转导。 FKBP12 /雷帕霉素抑制作用的分子基础仍然不确定。 Raptor（mTOR的调节相关蛋白）是最近鉴定的mTOR结合伴侣，对于体内mTOR信号转导至关重要，并且其与mTOR的结合对于体外mTOR催化的底物磷酸化至关重要。在这里，我们研究了内源性mTOR / raptor复合物在体内对雷帕霉素的反应以及在体外直接添加FKBP12 / rapapycin复合物的稳定性。雷帕霉素在体内可通过内源性或重组mTOR减少内源性猛禽的恢复;这种抑制作用要求mTOR具有结合FKBP12 /雷帕霉素复合物的能力，但与mTOR激酶活性无关。雷帕霉素在FKBP12的存在下直接在体外抑制了猛禽与mTOR的缔合，并同时降低了mTOR催化的猛禽依赖性但非猛禽依赖性底物的磷酸化。 mTOR自磷酸化未改变。这些观察结果表明雷帕霉素至少部分地通过抑制猛禽与mTOR的相互作用来抑制mTOR功能。该作用将mTOR与底物解偶联，并抑制mTOR信号传导，而不会改变mTOR的固有催化活性。

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