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

Aggie Lawer, Luke Schulz, Renata Sawyer, Xuyu Liu

Cells 2024 Feb 28

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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.

Citation

Aggie Lawer, Luke Schulz, Renata Sawyer, Xuyu Liu. Harmony of Protein Tags and Chimeric Molecules Empowers Targeted Protein Ubiquitination and Beyond. Cells. 2024 Feb 28;13(5)