E2 Ubiquitin Conjugating Enzymes

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The ubiquitin-conjugating enzyme, also known as E2 enzymes, are rarely referred to as ubiquitin-carrier enzymes, performs the second step of the ubiquitin reaction, which degrades the target protein through proteasomes.

Introduction

In the process of ubiquitin, ubiquitin-conjugating E2 enzyme plays a very important role and is an indispensable intermediate link. Ubiquitin-conjugating E2 enzyme is a multi-gene family, the number of which has expanded to about 100. There is diversity among its members in terms of molecular weight, structure and function. But they all contain a conservative domain-UBC domain. Ubiquitin-conjugating enzyme E2 can be further divided into four categories: some have only UBC domains to form E2 as class I, and they need E3 for substrate recognition. Except for the core domain, those with extensions at the C-terminal belong to class II. Those with extensions at the N-terminal belong to class III. Those with extension regions at both the C-terminal and the N-terminal belong to class IV.

Mechanism

There is a conserved cysteine residue in the UBC domain of ubiquitin-conjugating enzyme E2. As an active site, this Cys residue forms a thioester bond with ubiquitin molecule (Ub). Ubiquitin activating enzyme E1 transfers the ubiquitin to the cysteine active site of E2 to form the Ub-E2 complex, then either directly binds the substrate to connect ubiquitin to the target protein, or interacts with ubiquitin ligase E3 to transfer ubiquitin to the target protein.

Application

E2 is not only the carrier of UB, it has two functions: transmercaptan (transfer of thioester to mercapto) and aminolysis (transfer of thioester to amino). In cells, E 2 exists mainly in the form of E2~UB conjugates so that they can react at any time. In addition, E2 can also directly regulate the activity of ubiquitin-related enzymes. For example, the activity of OTUB1, a deubiquitin enzyme that hydrolyzes the Lys48 polyubiquitin chain, is enhanced by the interaction with free E2.

At present, about 40 E2 inhibitors have been found, which have stronger specificity and greater value in tumor therapy than only two E2 inhibitors. For example, compound CC0651 is an inhibitor of ubiquitin-conjugating enzyme E2 CDC34, which binds to CDC34 and causes conformational changes, thus unable to complete the transmission of UB. Although the effect of CC0651 in vitro experiment is good, there are still many difficulties to be overcome before practical application.

References:

1. Wiener, R., DiBello, A. T., Lombardi, P. M., Guzzo, C. M., Zhang, X., Matunis, M. J., & Wolberger, C. (2013). E2 ubiquitin-conjugating enzymes regulate the deubiquitinating activity of OTUB1. Nature structural & molecular biology, 20(9), 1033.
2. Alvinez, N. (2020). The effects of E2 enzyme mutations on the glutamate receptor GLR-1 in the endoplasmic reticulum-associated protein degradation (ERAD) pathway in C. elegans.

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