人 mTOR 复合物 I 的结构及其对雷帕霉素抑制的影响。
Structure of the human mTOR complex I and its implications for rapamycin inhibition.
机构信息
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
出版信息
Mol Cell. 2010 Jun 11;38(5):768-74. doi: 10.1016/j.molcel.2010.05.017.
Abstract
The mammalian target of rapamycin complex 1 (mTORC1) regulates cell growth in response to the nutrient and energy status of the cell, and its deregulation is common in human cancers. Little is known about the overall architecture and subunit organization of this essential signaling complex. We have determined the three-dimensional (3D) structure of the fully assembled human mTORC1 by cryo-electron microscopy (cryo-EM). Our analyses reveal that mTORC1 is an obligate dimer with an overall rhomboid shape and a central cavity. The dimeric interfaces are formed by interlocking interactions between the mTOR and raptor subunits. Extended incubation with FKBP12-rapamycin compromises the structural integrity of mTORC1 in a stepwise manner, leading us to propose a model in which rapamycin inhibits mTORC1-mediated phosphorylation of 4E-BP1 and S6K1 through different mechanisms.
摘要
哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）可响应细胞的营养和能量状态调节细胞生长，其失调在人类癌症中很常见。目前对于这种重要信号复合物的整体结构和亚基组成知之甚少。我们通过冷冻电镜（cryo-EM）确定了完全组装的人 mTORC1 的三维（3D）结构。我们的分析表明，mTORC1 是一个必需的二聚体，具有菱形整体形状和中央腔。二聚体界面是通过 mTOR 和 raptor 亚基之间的互锁相互作用形成的。与 FKBP12-雷帕霉素的长时间孵育会以逐步的方式破坏 mTORC1 的结构完整性，这使我们提出了一个模型，其中雷帕霉素通过不同的机制抑制 mTORC1 介导的 4E-BP1 和 S6K1 的磷酸化。
相似文献
1
Structure of the human mTOR complex I and its implications for rapamycin inhibition.人 mTOR 复合物 I 的结构及其对雷帕霉素抑制的影响。
Mol Cell. 2010 Jun 11;38(5):768-74. doi: 10.1016/j.molcel.2010.05.017.
2
PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding.PRAS40通过作为底物结合的直接抑制剂来调节mTORC1激酶活性。
J Biol Chem. 2007 Jul 6;282(27):20036-44. doi: 10.1074/jbc.M702376200. Epub 2007 May 17.
3
Rapamycin inhibits cytoskeleton reorganization and cell motility by suppressing RhoA expression and activity.雷帕霉素通过抑制 RhoA 的表达和活性来抑制细胞骨架重组和细胞迁移。
J Biol Chem. 2010 Dec 3;285(49):38362-73. doi: 10.1074/jbc.M110.141168. Epub 2010 Oct 11.
4
Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40.RHEB 激活 mTORC1 的机制和 PRAS40 对其的抑制作用。
Nature. 2017 Dec 21;552(7685):368-373. doi: 10.1038/nature25023. Epub 2017 Dec 13.
5
4.4 Å Resolution Cryo-EM structure of human mTOR Complex 1.人源mTOR复合物1的4.4埃分辨率冷冻电镜结构
Protein Cell. 2016 Dec;7(12):878-887. doi: 10.1007/s13238-016-0346-6. Epub 2016 Dec 1.
6
Site-specific mTOR phosphorylation promotes mTORC1-mediated signaling and cell growth.位点特异性mTOR磷酸化促进mTORC1介导的信号传导和细胞生长。
Mol Cell Biol. 2009 Aug;29(15):4308-24. doi: 10.1128/MCB.01665-08. Epub 2009 Jun 1.
7
The proline-rich Akt substrate of 40 kDa (PRAS40) is a physiological substrate of mammalian target of rapamycin complex 1.富含脯氨酸的40kDa Akt底物（PRAS40）是雷帕霉素复合物1哺乳动物靶点的生理底物。
J Biol Chem. 2007 Jul 13;282(28):20329-39. doi: 10.1074/jbc.M702636200. Epub 2007 May 21.
8
Curcumin disrupts the Mammalian target of rapamycin-raptor complex.姜黄素破坏雷帕霉素哺乳动物靶标- Raptor复合物。
Cancer Res. 2009 Feb 1;69(3):1000-8. doi: 10.1158/0008-5472.CAN-08-2367. Epub 2009 Jan 27.
9
LKB1 and AMP-activated protein kinase control of mTOR signalling and growth.LKB1 和 AMP 激活的蛋白激酶对 mTOR 信号和生长的控制。
Acta Physiol (Oxf). 2009 May;196(1):65-80. doi: 10.1111/j.1748-1716.2009.01972.x. Epub 2009 Feb 19.
10
Not all substrates are treated equally: implications for mTOR, rapamycin-resistance and cancer therapy.并非所有底物都受到同等对待：对mTOR、雷帕霉素抗性及癌症治疗的影响。
Cell Cycle. 2009 Feb 15;8(4):567-72. doi: 10.4161/cc.8.4.7659. Epub 2009 Feb 18.
引用本文的文献
1
The Precision-Guided Use of PI3K Pathway Inhibitors for the Treatment of Solid Malignancies.PI3K 通路抑制剂在实体恶性肿瘤治疗中的精准应用
Biomedicines. 2025 May 28;13(6):1319. doi: 10.3390/biomedicines13061319.
2
Quantitative Proteomics Unveils the Synergistic Effects of Combination Drugs on Cytoskeleton Composition and Autophagy-Mediated Cell Death in Neuroblastoma.定量蛋白质组学揭示联合用药对神经母细胞瘤细胞骨架组成和自噬介导的细胞死亡的协同作用。
J Proteome Res. 2025 Jul 4;24(7):3578-3596. doi: 10.1021/acs.jproteome.5c00191. Epub 2025 Jun 17.
3
mTOR controls ependymal cell differentiation by targeting the alternative cell cycle and centrosomal proteins.mTOR通过靶向替代细胞周期和中心体蛋白来控制室管膜细胞分化。
EMBO Rep. 2025 Apr 30. doi: 10.1038/s44319-025-00460-2.
4
TSC-mTORC1 Pathway in Postnatal V-SVZ Neurodevelopment.产后室管膜下区-脑室下区神经发育中的结节性硬化症-哺乳动物雷帕霉素靶蛋白复合物1信号通路
Biomolecules. 2025 Apr 12;15(4):573. doi: 10.3390/biom15040573.
5
(-)-Epicatechin Rescues Memory Deficits by Activation of Autophagy in a Mouse Model of Tauopathies.（-）-表儿茶素通过激活自噬在Tau蛋白病小鼠模型中挽救记忆缺陷。
MedComm (2020). 2025 Mar 24;6(4):e70144. doi: 10.1002/mco2.70144. eCollection 2025 Apr.
6
JC virus small tumor antigen promotes S phase entry and cell cycle progression.JC病毒小肿瘤抗原促进S期进入和细胞周期进程。
Tumour Virus Res. 2024 Dec;18:200298. doi: 10.1016/j.tvr.2024.200298. Epub 2024 Nov 23.
7
Phosphatidic acid directly activates mTOR and then regulates SREBP to promote ganoderic acid biosynthesis under heat stress in Ganoderma lingzhi.在灵芝中，磷酸脂酸直接激活 mTOR，然后调控 SREBP 以促进热应激下灵芝酸的生物合成。
Commun Biol. 2024 Nov 13;7(1):1503. doi: 10.1038/s42003-024-07225-y.
8
Mitophagy Unveiled: Exploring the Nexus of Mitochondrial Health and Neuroendocrinopathy.自噬揭示：探索线粒体健康与神经内分泌病理学的关联。
J Mol Neurosci. 2024 Nov 8;74(4):107. doi: 10.1007/s12031-024-02280-w.
9
mTORC1 signaling and diabetic kidney disease.mTORC1信号传导与糖尿病肾病
Diabetol Int. 2024 Jun 20;15(4):707-718. doi: 10.1007/s13340-024-00738-1. eCollection 2024 Oct.
10
The "Road" to Malignant Transformation from Endometriosis to Endometriosis-Associated Ovarian Cancers (EAOCs): An mTOR-Centred Review.从子宫内膜异位症到子宫内膜异位症相关卵巢癌（EAOC）的恶性转化之路：以mTOR为中心的综述
Cancers (Basel). 2024 Jun 6;16(11):2160. doi: 10.3390/cancers16112160.
本文引用的文献
1
Crystal structure of DNA-PKcs reveals a large open-ring cradle comprised of HEAT repeats.DNA-PKcs 的晶体结构揭示了由 HEAT 重复序列组成的大型开放式环摇篮。
Nature. 2010 Jan 7;463(7277):118-21. doi: 10.1038/nature08648. Epub 2009 Dec 20.
2
Molecular mechanisms of mTOR-mediated translational control.mTOR介导的翻译控制的分子机制。
Nat Rev Mol Cell Biol. 2009 May;10(5):307-18. doi: 10.1038/nrm2672. Epub 2009 Apr 2.
3
Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2.mTOR的活性位点抑制剂靶向mTORC1和mTORC2的雷帕霉素抗性输出。
PLoS Biol. 2009 Feb 10;7(2):e38. doi: 10.1371/journal.pbio.1000038.
4
An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1.一种ATP竞争性的雷帕霉素哺乳动物靶点抑制剂揭示了mTORC1的雷帕霉素抗性功能。
J Biol Chem. 2009 Mar 20;284(12):8023-32. doi: 10.1074/jbc.M900301200. Epub 2009 Jan 15.
5
Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation.雷帕霉素差异性抑制S6Ks和4E-BP1，以介导细胞类型特异性的mRNA翻译抑制。
Proc Natl Acad Sci U S A. 2008 Nov 11;105(45):17414-9. doi: 10.1073/pnas.0809136105. Epub 2008 Oct 27.
6
The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1.Rag GTP酶结合 Raptor 并介导氨基酸信号传导至 mTORC1。
Science. 2008 Jun 13;320(5882):1496-501. doi: 10.1126/science.1157535. Epub 2008 May 22.
7
Structure of TOR and its complex with KOG1.TOR的结构及其与KOG1的复合物。
Mol Cell. 2007 Aug 3;27(3):509-16. doi: 10.1016/j.molcel.2007.05.040.
8
Defining the role of mTOR in cancer.确定mTOR在癌症中的作用。
Cancer Cell. 2007 Jul;12(1):9-22. doi: 10.1016/j.ccr.2007.05.008.
9
PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding.PRAS40通过作为底物结合的直接抑制剂来调节mTORC1激酶活性。
J Biol Chem. 2007 Jul 6;282(27):20036-44. doi: 10.1074/jbc.M702376200. Epub 2007 May 17.
10
PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase.PRAS40是一种受胰岛素调节的mTORC1蛋白激酶抑制剂。
Mol Cell. 2007 Mar 23;25(6):903-15. doi: 10.1016/j.molcel.2007.03.003.
Zotero 插件