Figure 2.

Mechanism of proteolysis-targeting chimera (PROTAC) and “Modified” PROTAC. (A) Proteolysis-targeting chimaera (PROTAC) are bifunctional molecules, whose one end binds to the protein of interest (POI) while the other recruits E3 ligase forming a ternary complex. The E3 ligase induces proximity-induced ubiquitination of POI by transferring the ubiquitin (Ub) molecules from E2 enzyme to the POI, thus facilitating its degradation; (B) Representation of a hypothetical figure where technology can be modified to rescue the functional misfolded proteins undergoing rapid degradation in inherited metabolic disorders like PKU and HT1 having partial functions, causing deficiency of available protein for cellular functions. Hence, a PROTAC can be designed whose one end binds to the misfolded POI and the other binds to a ligand that can recruit the regulatory DUB. The DUBs will cleave off the ubiquitin molecule, avoiding the protein degradation, and will help to maintain a pool of protein required for normal cellular function.