How to Inactivate Human Ubiquitin E3 Ligases by Mutation.

Cristina Garcia-Barcena,Ugo Mayor,Juanma Ramirez,Nerea Osinalde

doi:10.3389/fcell.2020.00039

Cristina Garcia-Barcena, Ugo Mayor + Show 2 more

Open Access

https://doi.org/10.3389/fcell.2020.00039

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Abstract

E3 ubiquitin ligases are the ultimate enzymes involved in the transfer of ubiquitin to substrate proteins, a process that determines the fate of the modified protein. Numerous diseases are caused by defects in the ubiquitin-proteasome machinery, including when the activity of a given E3 ligase is hampered. 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. 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. Nevertheless, it is not always trivial to predict which mutation(s) will block the catalytic activity of a ligase. Here we review over 250 site-specific inactivating mutations that have been carried out in 120 human E3 ubiquitin ligases. We foresee that the information gathered here will be helpful for the design of future experimental strategies.

Highlights

Specialty section: This article was submitted to Cellular Biochemistry, a section of the journal Frontiers in Cell and Developmental
In this review we aim to provide a detailed description of mutations in ubiquitin E3 ligases, with the outlook that such detailed and structured catalog of mutants will provide a pattern to be considered by future researchers when designing new mutations on their E3 ligases
Mutations on E3 ligases have been associated with a number of diseases, including neurological disorders (George et al, 2018; Osinalde et al, 2019)

Summary

Introduction

Specialty section: This article was submitted to Cellular Biochemistry, a section of the journal Frontiers in Cell and Developmental. E3 ubiquitin ligases are the ultimate enzymes involved in the transfer of ubiquitin to substrate proteins, a process that determines the fate of the modified protein. 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 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. Ubiquitinmediated cellular responses will depend on the specific residues of the substrate that are modified and on the topology of the ubiquitin chains that are formed

Objectives

Conclusion