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C-terminal modification and functionalization of proteins via a self-cleavage tag triggered by a small molecule

Author

Listed:
  • Yue Zeng

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Wei Shi

    (Chinese Academy of Sciences)

  • Zhi Liu

    (Chinese Academy of Sciences
    Nanjing University of Chinese Medicine)

  • Hao Xu

    (Nanjing University of Chinese Medicine)

  • Liya Liu

    (Chinese Academy of Sciences)

  • Jiaying Hang

    (Chinese Academy of Sciences)

  • Yongqin Wang

    (Hangzhou Institute of Advanced Study)

  • Mengru Lu

    (Hangzhou Institute of Advanced Study)

  • Wei Zhou

    (Hangzhou Institute of Advanced Study)

  • Wei Huang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Nanjing University of Chinese Medicine
    Hangzhou Institute of Advanced Study)

  • Feng Tang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Hangzhou Institute of Advanced Study)

Abstract

The precise modification or functionalization of the protein C-terminus is essential but full of challenges. Herein, a chemical approach to modify the C-terminus is developed by fusing a cysteine protease domain on the C-terminus of the protein of interest, which could achieve the non-enzymatic C-terminal functionalization by InsP6-triggered cysteine protease domain self-cleavage. This method demonstrates a highly efficient way to achieve protein C-terminal functionalization and is compatible with a wide range of amine-containing molecules and proteins. Additionally, a reversible C-terminal de-functionalization is found by incubating the C-terminal modified proteins with cysteine protease domain and InsP6, providing a tool for protein functionalization and de-functionalization. Last, various applications of protein C-terminal functionalization are provided in this work, as demonstrated by the site-specific assembly of nanobody drug conjugates, the construction of a bifunctional antibody, the C-terminal fluorescent labeling, and the C-terminal transpeptidation and glycosylation.

Suggested Citation

  • Yue Zeng & Wei Shi & Zhi Liu & Hao Xu & Liya Liu & Jiaying Hang & Yongqin Wang & Mengru Lu & Wei Zhou & Wei Huang & Feng Tang, 2023. "C-terminal modification and functionalization of proteins via a self-cleavage tag triggered by a small molecule," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42977-x
    DOI: 10.1038/s41467-023-42977-x
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    References listed on IDEAS

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    1. M. A. Jackson & E. K. Gilding & T. Shafee & K. S. Harris & Q. Kaas & S. Poon & K. Yap & H. Jia & R. Guarino & L. Y. Chan & T. Durek & M. A. Anderson & D. J. Craik, 2018. "Molecular basis for the production of cyclic peptides by plant asparaginyl endopeptidases," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
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