Activation of mTORC1 in two steps: Rheb-GTP activation of catalytic function and increased binding of substrates to raptor
Activation of mTORC1 in two steps: Rheb-GTP activation of catalytic function and increased binding of substrates to raptor
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DOI：
10.1042/bst0370223
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发表时间：
2009-02-01
影响因子：
3.9
通讯作者：
Kikkawa, Ushio
中科院分区：
文献类型：
--
作者：
Avruch, Joseph;Long, Xiaomeng;Kikkawa, Ushio
mTOR复合物1的信号传导功能由Rheb-GTP激活，Rheb-GTP通过不完全理解的机制控制mTOR（雷帕霉素的哺乳动物靶标）激酶结构域的催化能力。Rheb可以直接与mTOR激酶结构域结合，并与失活的核苷酸缺陷型Rheb突变体结合，使mTOR处于催化失活状态。然而，除了mTOR以外的Rheb-GTP靶点，如FKBP 38（FK 506结合蛋白38）和/或PLD 1（磷脂酶D（1）），也可能有助于mTOR激活。一旦被激活，mTOR催化结构域仅在底物与raptor（mTOR的调节相关蛋白）结合时磷酸化底物，raptor是复合物内的一种单独多肽。胰岛素/营养物刺激mTOR复合物1信号传导的机制，除了Rheb-GTP激活mTOR催化功能外，还涉及mTORC 1（mTOR复合物1）构型的稳定修饰，这增加了底物接近其在猛禽多肽上的结合位点。mTORC 1激活第二步的机制尚不清楚。
The signalling function of mTOR complex 1 is activated by Rheb-GTP, which controls the catalytic competence of the mTOR (mammalian target of rapamycin) kinase domain by an incompletely understood mechanism. Rheb can bind directly to the mTOR kinase domain, and association with inactive nucleotide-deficient Rheb mutants traps mTOR in a catalytically inactive state. Nevertheless, Rheb-GTP targets other than mTOR, such as FKBP38 (FK506-binding protein 38) and/or PLD1 (phospholipase D(1)), may also contribute to mTOR activation. Once activated, the mTOR catalytic domain phosphorylates substrates only when they are bound to raptor (regulatory associated protein of mTOR), a separate polypeptide within the complex. The mechanism of insulin/nutrient stimulation of mTOR complex 1 signalling, in addition to Rheb-GTP activation of the mTOR catalytic function, also involves a stable modification of the configuration of mTORC1 (mTOR complex 1) that increases access of substrates to their binding site on the raptor polypeptide. The mechanism underlying this second step in the activation of mTORC1 is unknown.