Ubiquitin recruiting chimera: more than just a PROTAC

• Published in: Biology direct Vol. 19; no. 1; pp. 55 - 12
• Main Authors: Grigoreva, Tatyana A, Novikova, Daria S, Melino, Gerry, Barlev, Nick A, Tribulovich, Vyacheslav G
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 09.07.2024; BioMed Central; BMC
• Subjects: Apoptosis; Biodegradation; Biological effects; Biomolecules; Cell cycle; Chemical properties; Chimeras; Clinical trials; Degradation; Enzymes; Health aspects; Humans; Kinases; Ligands; Polypeptides; PROTAC; Protein degradation; Protein interaction; Protein research; Protein therapy; Protein transport; Protein-protein interactions; Proteins; Proteolysis; Review; Substrates; Ubiquitin; Ubiquitin - metabolism; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Russia; Ubiquitin; PROTAC; Protein degradation
• ISSN: 1745-6150; 1745-6150
• DOI: 10.1186/s13062-024-00497-8

Ubiquitinylation of protein substrates results in various but distinct biological consequences, among which ubiquitin-mediated degradation is most well studied for its therapeutic application. Accordingly, artificially targeted ubiquitin-dependent degradation of various proteins has evolved into the therapeutically relevant PROTAC technology. This tethered ubiquitinylation of various targets coupled with a broad assortment of modifying E3 ubiquitin ligases has been made possible by rational design of bi-specific chimeric molecules that bring these proteins in proximity. However, forced ubiquitinylation inflicted by the binary warheads of a chimeric PROTAC molecule should not necessarily result in protein degradation but can be used to modulate other cellular functions. In this respect it should be noted that the ubiquitinylation of a diverse set of proteins is known to control their transport, transcriptional activity, and protein-protein interactions. This review provides examples of potential PROTAC usage based on non-degradable ubiquitinylation.