为了了解mTORC2如何识别底物，课题组研究人员创建了半合成探针来捕获mTORC2-Akt复合物并确定其结构。虽然大多数蛋白激酶识别磷酸化位点附近的氨基酸，但局部序列对mTORC2识别底物的贡献很小。相反，特异性决定因素是Akt的二级和三级结构元件，这些元件将mTORC2组分mSin1结合到mTOR活性位点的远端，并且在至少18个相关底物中保守。这些结果揭示了mTORC2如何识别其典型底物，并可能使mTORC2特异性抑制剂的设计成为可能。
据介绍，mTOR蛋白激酶形成两个多蛋白复合物，mTORC1和mTORC2，它们在不同的信号通路中起作用。mTORC1受营养物质调节，mTORC2是磷酸肌醇-3激酶（PI3K）和小鸟苷三磷酸Ras信号网络的中心节点，通常在癌症和糖尿病中失调。尽管mTOR在体外磷酸化许多底物，但在细胞中，mTORC1和mTORC2具有高特异性：mTORC2磷酸化蛋白激酶Akt和PKC，但不磷酸化与mTORC1底物密切相关的激酶。
附：英文原文
Title: Structural basis for the recruitment and selective phosphorylation of Akt by mTORC2
Author: Martin S. Taylor, Maggie Chen, Matthew Hancock, Maximilian Wranik, Bryant D. Miller, Timothy R. O’Meara, Brad A. Palanski, Scott B. Ficarro, Brian J. Groendyke, Yufei Xiang, Kazuma T. Kondo, Karen Y. Linde-Garelli, Michelle J. Lee, Dibyendu Mondal, Daniel Freund, Samantha Congreve, Kaay Matas, Maximiliaan Hennink, Kera Xibinaku, Max L. Valenstein, Trevor van Eeuwen, Jarrod A. Marto, Andrej Sali, Yi Shi, Nathanael S. Gray, David M. Sabatini, Nam Chu, Kacper B. Rogala, Philip A. Cole
Issue&Volume: 2025-11-27
Abstract: The mTOR protein kinase forms two multiprotein complexes, mTORC1 and mTORC2, that function in distinct signaling pathways. mTORC1 is regulated by nutrients, and mTORC2 is a central node in phosphoinositide-3 kinase (PI3K) and small guanosine triphosphate Ras signaling networks commonly deregulated in cancer and diabetes. Although mTOR phosphorylates many substrates in vitro, in cells, mTORC1 and mTORC2 have high specificity: mTORC2 phosphorylates the protein kinases Akt and PKC, but not closely related kinases that are mTORC1 substrates. To understand how mTORC2 recognizes substrates, we created semisynthetic probes to trap the mTORC2-Akt complex and determine its structure. Whereas most protein kinases recognize amino acids adjacent to the phosphorylation site, local sequence contributes little to substrate recognition by mTORC2. Instead, the specificity determinants were secondary and tertiary structural elements of Akt that bound the mTORC2 component mSin1 distal to the mTOR active site and were conserved amongst at least 18 related substrates. These results reveal how mTORC2 recognizes its canonical substrates and may enable the design of mTORC2-specific inhibitors.
DOI: adv7111
Source: https://www.science.org/doi/10.1126/science.adv7111