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Cryo-EM structures reveal the dynamic transformation of human alpha-2-macroglobulin working as a protease inhibitor

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Abstract

Human alpha-2-macroglobulin is a well-known inhibitor of a broad spectrum of proteases and plays important roles in immunity, inflammation, and infections. Here, we report the cryo-EM structures of human alpha-2-macroglobulin in its native state, induced state transformed by its authentic substrate, human trypsin, and serial intermediate states between the native and fully induced states. These structures exhibit distinct conformations, which reveal the dynamic transformation of alpha-2-macro-globulin that acts as a protease inhibitor. The results shed light on the molecular mechanism of alpha-2-macroglobulin in entrapping substrates.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (31971154, 31730023, 31521002), the Chinese Ministry of Science and Technology (2017YFA0504700, 2021YFA1300100), the Chinese Academy of Sciences (CAS) (XDB37010100), and the National Laboratory of Biomacromolecules of China (2019KF07). We thank Jianhui Li, Zhenwei Yang, Yuanyuan Chen, and Xiaoxia Yu at the Core Facility for Protein Research (Institute of Biophysics, Chinese Academy of Sciences) for assistance with CD and ITC experiments; Gang Ji, Xiaojun Huang, Boling Zhu, Xujing Li at the Center for Biological Imaging (CBI), Core Facility for Protein Sciences, Chinese Academy of Sciences for assistance with EM data collection; and Jifeng Wang, Zhensheng Xie, Xiang Ding, Mengmeng Zhang (Proteomics, Institute of Biophysics, Chinese Academy of Sciences) for assistance with the Q-Exactive mass spectrometer analysis.

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Authors and Affiliations

  1. National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China

    Xiaoxing Huang, Youwang Wang, Cong Yu, Hui Zhang, Xinxin Li, Kai Song, Min Zhou & Ping Zhu

  2. The Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, 100193, China

    Qiang Ru

  3. University of Chinese Academy of Sciences, Beijing, 100049, China

    Youwang Wang, Cong Yu, Hui Zhang, Xinxin Li & Ping Zhu

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  1. Xiaoxing Huang
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Huang, X., Wang, Y., Yu, C. et al. Cryo-EM structures reveal the dynamic transformation of human alpha-2-macroglobulin working as a protease inhibitor. Sci. China Life Sci. 65, 2491–2504 (2022). https://doi.org/10.1007/s11427-022-2139-2

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