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Review

Harmony of Protein Tags and Chimeric Molecules Empowers Targeted Protein Ubiquitination and Beyond

by
Aggie Lawer
1,2,
Luke Schulz
1,
Renata Sawyer
1,2 and
Xuyu Liu
1,2,*
1
School of Chemistry, Faculty of Science, The University of Sydney, Camperdown, NSW 2050, Australia
2
Heart Research Institute, The University of Sydney, Newtown, NSW 2042, Australia
*
Author to whom correspondence should be addressed.
Cells 2024, 13(5), 426; https://doi.org/10.3390/cells13050426
Submission received: 26 January 2024 / Revised: 23 February 2024 / Accepted: 26 February 2024 / Published: 28 February 2024

Abstract

Post-translational modifications (PTMs) are crucial mechanisms that underlie the intricacies of biological systems and disease mechanisms. This review focuses on the latest advancements in the design of heterobifunctional small molecules that hijack PTM machineries for target-specific modifications in living systems. A key innovation in this field is the development of proteolysis-targeting chimeras (PROTACs), which promote the ubiquitination of target proteins for proteasomal degradation. The past decade has seen several adaptations of the PROTAC concept to facilitate targeted (de)phosphorylation and acetylation. Protein fusion tags have been particularly vital in these proof-of-concept studies, aiding in the investigation of the functional roles of post-translationally modified proteins linked to diseases. This overview delves into protein-tagging strategies that enable the targeted modulation of ubiquitination, phosphorylation, and acetylation, emphasizing the synergies and challenges of integrating heterobifunctional molecules with protein tags in PTM research. Despite significant progress, many PTMs remain to be explored, and protein tag-assisted PTM-inducing chimeras will continue to play an important role in understanding the fundamental roles of protein PTMs and in exploring the therapeutic potential of manipulating protein modifications, particularly for targets not yet addressed by existing drugs.
Keywords: post-translational modification; ubiquitination; PROTAC; dTAG; proximity; phosphorylation; acetylation post-translational modification; ubiquitination; PROTAC; dTAG; proximity; phosphorylation; acetylation

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MDPI and ACS Style

Lawer, A.; Schulz, L.; Sawyer, R.; Liu, X. Harmony of Protein Tags and Chimeric Molecules Empowers Targeted Protein Ubiquitination and Beyond. Cells 2024, 13, 426. https://doi.org/10.3390/cells13050426

AMA Style

Lawer A, Schulz L, Sawyer R, Liu X. Harmony of Protein Tags and Chimeric Molecules Empowers Targeted Protein Ubiquitination and Beyond. Cells. 2024; 13(5):426. https://doi.org/10.3390/cells13050426

Chicago/Turabian Style

Lawer, Aggie, Luke Schulz, Renata Sawyer, and Xuyu Liu. 2024. "Harmony of Protein Tags and Chimeric Molecules Empowers Targeted Protein Ubiquitination and Beyond" Cells 13, no. 5: 426. https://doi.org/10.3390/cells13050426

APA Style

Lawer, A., Schulz, L., Sawyer, R., & Liu, X. (2024). Harmony of Protein Tags and Chimeric Molecules Empowers Targeted Protein Ubiquitination and Beyond. Cells, 13(5), 426. https://doi.org/10.3390/cells13050426

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