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.

DOI:10.1016/j.molcel.2010.05.017

PMID:20542007

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2887672/

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。