The ubiquitination reaction requires the coordinated action of three types of enzymes termed E1, E2, and E3. But protein ubiquitination participates in a plethora of additional cellular responses including regulation of gene expression, cell signalling, cell cycle, DNA repair and apoptosis ( Pickart, 2001 Gilberto and Peter, 2017). Frequently, ubiquitinated proteins are targeted for degradation through the proteasomal system on an ATP hydrolysis-dependent manner ( Hershko and Ciechanover, 1998 Komander and Rape, 2012). Proteins are covalently modified on their Lys residues with ubiquitin via amide isopeptide linkages ( Laney and Hochstrasser, 1999). Ubiquitin is a 76-amino-acid protein, highly conserved among organisms ( Zuin et al., 2014), used–through the ubiquitin-proteasome system- to regulate many cellular processes.
#IDOL MANAGER BETA 21.3 CODE#
Ubiquitination, the Ubiquitin Code and E3 Ligases We foresee that the information gathered here will be helpful for the design of future experimental strategies. Here we review over 250 site-specific inactivating mutations that have been carried out in 120 human E3 ubiquitin ligases. Nevertheless, it is not always trivial to predict which mutation(s) will block the catalytic activity of a ligase. For this purpose, site-specific mutation of key residues involved in either protein interaction, substrate recognition or ubiquitin transfer have been reported to successfully inactivate E3 ligases.
Thus, inactivation of E3 ligases and the resulting effects at molecular or cellular level have been the focus of many studies during the last few years.
Numerous diseases are caused by defects in the ubiquitin-proteasome machinery, including when the activity of a given E3 ligase is hampered.
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