E3 Ubiquitin Ligases

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Introduction

E3 is a large family, more than 600 E3 have been found. There are three main types of ubiquitin ligase E3: HECT (homologous to E6AP C-terminus) domain family, RING (really interesting new gene) domain family, and U-box protein family. The HECT domain acts mainly through the thioester bond necessary for the formation of ubiquitin. The RING domain provides residence sites for E2 and the substrate to catalyze the transfer of ubiquitin to the substrate. The ubiquitin ligase E3 of the U-box family is necessary for post-translational quality control of eukaryotic proteins.

Mechanism

E3 is a ubiquitin ligase, which directly or indirectly catalyzes the transfer of ubiquitin to the target protein (substrate) and forms isopeptide bonds. In general, ubiquitin ligase can make the target protein multi-ubiquitin, that is, adding multiple ubiquitin molecules to form a multi-ubiquitin chain, and the protein with multi-ubiquitin chain can be recognized by proteasome and degraded. However, in some cases, ubiquitin ligase connects only one ubiquitin molecule to the target protein, this single ubiquitin protein will not be degraded by proteasome, but its location or function in cells may be changed. For example, mono-ubiquitin proteins can change their position by binding to other proteins with ubiquitin-binding domains.

Application

Compared with E1 and E2, E3 has attracted more attention, not only because of the large number of E3, but also because E3 can specifically recognize protein substrates, so it can be used as a therapeutic target for a variety of E3-related diseases, including human tumors. E3 is more specific. E3 is full of carcinogenic factors, tumor suppressor factors, and some can be converted into each other under specific conditions. For example, in many human tumors, tumor suppressor Fbw7 is often lost or mutated, so regulating its upstream factor to restore the function of Fbw7 is one of the ways of tumor therapy. Skp2 can achieve its carcinogenic effect by degrading tumor suppressor, making cancer cells proliferate malignant. β-TRCP has two sides, and regulates the degradation of tumor suppressor or carcinogenic factors according to the environment. Drugs targeting E3, such as Serdemetan, LCL161 and AT-406, have entered clinical trials, and IMiDs has been approved by FDA.

References:

1. Mayer, J., Layfield, R., Ardley, H. C., & Robinson, P. A. (2005). E3 ubiquitin ligases. Essays in biochemistry, 41, 15-30.
2. Sun, Y. (2003). Targeting E3 ubiquitin ligases for cancer therapy. Cancer biology & therapy, 2(6), 623-629.

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