Proteasomal Degradation of Zn-Dependent Hdacs: The E3-Ligases Implicated and the Designed Protacs That Enable Degradation

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 ch...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2021-09, Vol.26 (18), p.5606
Main Authors: Márquez-Cantudo, Laura, Ramos, Ana, Coderch, Claire, de Pascual-Teresa, Beatriz
Format: Article
Language:English
Subjects:
Amino acids
Biodegradation
Cell cycle
Chromatin
Degradation
Design
drug design
E3-ligase
Endoplasmic reticulum
Enzymes
Gene expression
HDACs
Histone deacetylase
Homology
PROTACs
proteasomal degradation
Proteasomes
Proteins
Proteolysis
Review
Selectivity
Ubiquitin
Zinc
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Summary: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.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules26185606