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

Yue Zeng, Wei Shi, Zhi Liu, Hao Xu, Liya Liu, Jiaying Hang, Yongqin Wang, Mengru Lu, Wei Zhou, Wei Huang and Feng Tang ()
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Yue Zeng: Chinese Academy of Sciences
Wei Shi: Chinese Academy of Sciences
Zhi Liu: Chinese Academy of Sciences
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
Feng Tang: Chinese Academy of Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42977-x

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