斯坦福大学医学院Kacper B. Rogala小组在研究中取得进展。他们研制了氨基酸动态调控mTORC1的结构基础。相关论文于2025年8月20日发表在《自然》杂志上。

通过低温电子显微镜，该课题组研究人员确定了与Sestrin2或CASTOR1结合的稳定GATOR2的结构。这些传感器占据不同且不重叠的结合位点，其破坏选择性地损害了mTORC1感知单个氨基酸的能力。小组还解析了Sestrin2的载脂蛋白（无亮氨酸）结构，并表征了Sestrin2和CASTOR1中氨基酸诱导的结构重排，这些重排触发了它们与GATOR2的分离。任何一个传感器的结合限制了GATOR2的动态WDR24 β-推进器，这是营养依赖性mTORC1激活所必需的结构域。这些发现揭示了将氨基酸充足传递给GATOR2的变构机制，以及随后导致mTORC1激活的结构变化。

据了解，雷帕霉素复合物1（mTORC1）的机制靶点锚定了一个保守的信号通路，该信号通路根据营养可利用性调节生长。氨基酸通过Rag GTP酶激活mTORC1， GTP酶受GATOR调控，GATOR是一种由GATOR1、KICSTOR和营养感应中枢GATOR2组成的超复合体。GATOR2形成一个八角形笼，其独特的WD40结构域β-螺旋桨与GATOR1和亮氨酸传感器Sestrin1和Sestrin2 （SESN1和SESN2）以及精氨酸传感器CASTOR1相互作用。这些传感器调节GATOR2的机制，以及它们在结合同源氨基酸时如何与GATOR2分离，目前尚不清楚。

附：英文原文

Title: Structural basis for the dynamic regulation of mTORC1 by amino acids

Author: Valenstein, Max L., Wranik, Maximilian, Lalgudi, Pranav V., Linde-Garelli, Karen Y., Choi, Yuri, Chivukula, Raghu R., Sabatini, David M., Rogala, Kacper B.

Issue&Volume: 2025-08-20

Abstract: The mechanistic target of rapamycin complex 1 (mTORC1) anchors a conserved signalling pathway that regulates growth in response to nutrient availability1,2,3,4,5. Amino acids activate mTORC1 through the Rag GTPases, which are regulated by GATOR, a supercomplex consisting of GATOR1, KICSTOR and the nutrient-sensing hub GATOR2 (refs. 6,7,8,9). GATOR2 forms an octagonal cage, with its distinct WD40 domain β-propellers interacting with GATOR1 and the leucine sensors Sestrin1 and Sestrin2 (SESN1 and SESN2) and the arginine sensor CASTOR1 (ref. 10). The mechanisms through which these sensors regulate GATOR2 and how they detach from it upon binding their cognate amino acids remain unknown. Here, using cryo-electron microscopy, we determined the structures of a stabilized GATOR2 bound to either Sestrin2 or CASTOR1. The sensors occupy distinct and non-overlapping binding sites, disruption of which selectively impairs the ability of mTORC1 to sense individual amino acids. We also resolved the apo (leucine-free) structure of Sestrin2 and characterized the amino acid-induced structural rearrangements within Sestrin2 and CASTOR1 that trigger their dissociation from GATOR2. Binding of either sensor restricts the dynamic WDR24 β-propeller of GATOR2, a domain essential for nutrient-dependent mTORC1 activation. These findings reveal the allosteric mechanisms that convey amino acid sufficiency to GATOR2 and the ensuing structural changes that lead to mTORC1 activation.

DOI: 10.1038/s41586-025-09428-7

Source: https://www.nature.com/articles/s41586-025-09428-7