Selective protein degradation through tetrazine ligation of genetically incorporated unnatural amino acids

Chen, Jinghao, Dai, Gaocan, Duan, Shixiang, Huang, Yang, Wu, Yi‐Lin ORCID: https://orcid.org/0000-0003-0253-1625, Xie, Zhiyong and Tsai, Yu‐Hsuan 2024. Selective protein degradation through tetrazine ligation of genetically incorporated unnatural amino acids. Chemistry - An Asian Journal , e202400824. 10.1002/asia.202400824

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Abstract

Small molecule‐responsive tags for targeted protein degradation are valuable tools for fundamental research and drug target validation. Here, we show that genetically incorporated unnatural amino acids bearing a strained alkene or alkyne functionality can act as a minimalist tag for targeted protein degradation. Specifically, we observed the degradation of strained alkene‐ or alkyne‐containing kinases and E2 ubiquitin‐conjugating enzymes upon treatment with hydrophobic tetrazine conjugates. The extent of the induced protein degradation depends on the identity of the target protein, unnatural amino acid, and tetrazine conjugate, as well as the site of the unnatural amino acid in the target protein. Mechanistic studies revealed proteins undergo proteasomal degradation after tetrazine tethering, and the identity of tetrazine conjugates influences the dependence of ubiquitination on protein degradation. This work provides an alternative approach for targeted protein degradation and mechanistic insight, facilitating the future development of more effective targeted protein degradation strategies.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Chemistry
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/
Publisher:	Wiley
ISSN:	1861-4728
Date of First Compliant Deposit:	28 October 2024
Date of Acceptance:	29 August 2024
Last Modified:	12 Nov 2024 10:59
URI:	https://orca.cardiff.ac.uk/id/eprint/173436

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