Abstract
Protein degradation by the Ubiquitin-Proteasome System is one of the main mechanisms of the regulation of cellular proteostasis, and the E3 ligases are the key effectors for the protein recognition and degradation. Many E3 ligases have key roles in cell cycle regulation, acting as checkpoints and checkpoint regulators. One of the many important proteins involved in the regulation of the cell cycle are the members of the Histone Deacetylase (HDAC) family. The importance of zinc dependent HDACs in the regulation of chromatin packing and, therefore, gene expression, has made them targets for the design and synthesis of HDAC inhibitors. However, achieving potency and selectivity has proven to be a challenge due to the homology between the zinc dependent HDACs. PROteolysis TArgeting Chimaera (PROTAC) design has been demonstrated to be a useful strategy to inhibit and selectively degrade protein targets. In this review, we attempt to summarize the E3 ligases that naturally ubiquitinate HDACs, analyze their structure, and list the known ligands that can bind to these E3 ligases and be used for PROTAC design, as well as the already described HDAC-targeted PROTACs.
Highlights
Co-immuno precipitation assays carried out by De Smaele E. et al have demonstrated that both KCTD11 and KCTD21 promote the ubiquitination of HDAC1, whereas KCTD6 needs to recruit KCTD11 [45]
Selective Histone Deacetylase (HDAC) inhibition has become a popular topic in drug discovery, as HDACs are implicated in the development of many types of cancer, diabetes, and inflammatory, neurodegenerative, and cardiovascular diseases
Many researchers have attempted to address this challenge by the design and synthesis of HDAC-directed PROteolysis TArgeting Chimaera (PROTAC)
Summary
Proteins inside the cells are subjected to a well meshed quality control system that is comprised of the Ubiquitin-Proteasome System (UPS), autophagic lysosomes, and the endoplasmic reticulum. Depending on the position of the ubiquitinated lysine residues and the number of Ub molecules attached, the substrate protein will be marked for proteasomal or lysosome degradation, or to fulfill roles in cellular regulation. The RBR E3 ligases, despite having two RING domains and being structurally more similar to RING, have a mechanism of action which is more similar to that of the HECT E3 ligases (Figure 1) [9,12] Both the RING and U-box domains are responsible for binding the ubiquitin-carrying E2 ligase (Ub-E2) [13]. There is no evidence of E2 cooperation in dimeric RINGs, as they bind very far apart from one another [10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
